Benzoxazine antimicrobial agents

ABSTRACT

The invention relates to benzoxazine and pyrido-oxazine antibacterial compounds of the general formula: ##STR1## wherein the moiety Q is a fused phenyl or fused pyridyl moiety as herein described, pharmaceutical compositions containing the compounds, methods for their production and their use in treating bacterial infections.

This is a division of application Ser. No. 08/553,188, filed Nov. 7,1995, now U.S. Pat. No. 5,696,117, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The invention relates to benzoxazine and pyrido-oxazine antibacterialcompounds, pharmaceutical compositions containing the compounds, andmethods for their production and use. These compounds are effective ininhibiting the action of a bacterial histidine protein kinase and arethus useful as anti-infective agents against a variety of bacterialorganisms, including organisms which are resistant to other knownantibiotics.

BACKGROUND OF THE INVENTION

Prokaryotes regulate the transcription of many of their genes inresponse to changes in the organisms' environment (J. B. Stock, A. M.Stock, and J. M. Mottonen, Nature, 344, 395-400 (1990)). Such regulationis essential if the organism is to adapt itself to survival in achanging environment, and pathogenic bacteria rely on such regulatorysystems to enable them to survive within their host's body (J. F.Miller, J. J. Mekalanos, S. Falkow, Science, 243, 1059 (1989)). Chemicalcompounds that interfere with the regulatory mechanisms would beexpected to be useful anti-infective drugs, as they would preventbacteria from making necessary adaptive changes in their patterns ofgene expression.

Virulence, chemotaxis, toxin production, sporulation, and reproductionare examples of the bacterial processes that are under regulatorycontrol, and which could be inhibited by such compounds. The inhibitionof one or more of these processes is expected to lead to reducedvirulence, a slowing or halting of bacterial growth and reproduction,and even to bacterial cell death if vital functions are interrupted.

For example, it has been shown that Salmonella species express certainproteins, under regulatory control and in response to the presence ofintestinal epithelial cells, which enable them to adhere to and invadethese cells. Bacteria unable to synthesize these proteins are avirulent:they cannot cause infection in mice (B. B. Finlay, F. Heffron, S.Falkow, Science, 243, 940-943 (1989)). A similar effect would beexpected if the genes coding for these proteins were intact, butremained unexpressed.

To accomplish adaptive responses to the environment, bacteria rely onphosphorelay mechanisms, referred to in the art as "two-componentswitches." These switches have the net effect of transmittinginformation from the environment to the cell nucleus, where theinformation is responded to by the switching on or off of transcriptionof relevant genes. The first step of this phosphorelay scheme relies onnumerous histidine protein kinase (HPK) enzymes. Most of these HPKenzymes are sensor molecules, and respond to stimulation by specificenvironmental signals by transferring phosphate from ATP to a histidineresidue of the HPK protein. Some HPK enzymes are stimulated by thepresence of acceptor proteins (described below), the concentration ofwhich are modulated by environmental signals. In either case, thisauto-phosphorylation is followed by transfer of the phosphate to anaspartyl residue of one or more acceptor proteins (the second componentsof the two-component switch), which are either regulators of geneexpression (by binding to control regions on DNA, or to the RNApolymerase complex) or are themselves kinases for other acceptormolecules. These secondary acceptors may again be regulatory proteins,or kinases toward yet another protein. This cascade of phosphate fromprotein to protein eventually results in the phosphorylation of one ormore regulatory proteins, which then control gene expression.

Mammalian cells do not, or at least are not presently known to, utilizeHPK-driven phosphorelay systems for gene regulation. Thus, compoundswhich selectively inhibit either the autophosphorylation of the HPKprotein, or the phosphotransfer step(s), or both, would not be expectedto have undesirable effects on the host organism, and are promisingcandidates for antiinfective drugs. The emergence of drug-resistantpathogenic organisms that are resistant to one or more of the currentlyavailable drugs has created a need for novel antibiotics, that act bymechanisms unrelated to those of currently available agents, andinhibitors of HPK would fill this need. The presence of multipleHPK-driven systems (over fifty are currently known) in bacteria givesHPK inhibitors a potential advantage over current antibiotics, in thatmutations of a single HPK enzyme are unlikely to confer drug resistanceto an organism.

Recently, workers in this field reported a method for detectingbacterial "virulence" genes that are selectively expressed when bacteriainfect a host (M. J. Mahan, J. M. Slauch, and J. J. Mekalanos, Science,259, 686-688 (1993)). The potential use of this information in thedesign of new antibiotics was mentioned, but actual methods of reducingexpression of these genes were not described. A preliminary report fromanother group of workers disclosed inhibitors of the two-componentswitch controlling alginate gene activation in Pseudomonas aeruginosa inan in vitro system (S. Roychoudhury et al., Proc. Nat. Acad. Sci., 90,965-969 (1993)), but no anti-bacterial activity of the compounds wasreported.

SUMMARY OF THE INVENTION

The invention comprises compounds of general structure 1 shown below:##STR2## Wherein the moiety Q is a fused phenyl or fused pyridyl moiety;Z₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy,amino, nitro, sulfonylamino or trifluoromethyl;

Z₂ is hydrogen or a halogen;

X is hydrogen or oxygen;

A is C₁ -C₆ alkyl, C₁ -C₆ alkylaryl or C₁ -C₆ alkylheterocyclyl

wherein aryl is biphenyl, naphthyl or phenyl; and heterocyclyl is a 5 or6 membered saturated or unsaturated heterocyclic group containing 1-4nitrogen atoms, an oxygen or a sulfur atom;

wherein said aryl or heterocyclyl group is optionally substituted with(C₁ -C₆) alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen,dihalogen, nitro, amino, carboxyl, carbo(C₁ -C₄)alkoxy ormethylsulfonylamino;

n is an integer from 0-3;

Y is a moiety selected from:

(a) NHR₁ R₂, N+R₁ R₂ R₃ ; ##STR3## (c) CO₂ H, CHO; (d) CH(R₆)CO₂ H,CH(R₆)CO₂ CH₃, CH═CHR₇, CH═C(CO₂ H)₂ ;

(e) a moiety of the formula: ##STR4## (f) 5-tetrazolyl; wherein

R₁, R₂ and R₃ are independently hydrogen, C₁ -C₆ alkyl, ort-butoxycarbonyl;

R₄ and R₅ are independently t-butoxycarbonyl or hydrogen or R₄ and

R₅ may be joined together to form an imidazoline, imidazolyl orpyrimidine ring;

R₆ is hydrogen, hydroxy or chloro;

R₇ is CO₂ H or C(O)NH(CH₂)_(p) OH wherein p is an integer from 1-4;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

Another aspect of the invention comprises a method of treating bacterialinfections in mammals by administering to a mammal suffering from suchinfection a therapeutically effective amount of a compound selected fromthose of Formula 1 effective in inhibiting the action of a bacterialhistidine protein kinase.

The compounds of the present invention inhibit the autophosphorylationof bacterial histidine kinases; they also inhibit the transfer ofphosphate from phosphorylated histidine kinases to the aspartyl residuesof the phosphate acceptor proteins involved in regulation of bacterialgene expression. The compounds of the present invention have been foundto inhibit the growth of bacteria by the standard method, measurement ofminimum inhibitory concentrations (MIC values). The compounds are usefulas bacteriostatic and bactericidal agents, and as anti-infective agentsin the treatment of infectious diseases. They may also have utility inincreasing the sensitivity of bacteria to conventional antibiotics.

DETAILED DESCRIPTION

Relative to the above generic description, certain compounds of formula1 are preferred.

Preferred embodiments are those compounds wherein Q is fused phenyl.

Preferred groups for A are C₁ -C₅ alkyl, CH₂ phenyl, CH₂ thienyl, CH₂pyridyl, CH₂ furyl, or ethyl piperidine.

Preferred groups for Y are:

(a) NHR₁ R₂, N⁺ R₁ R₂ R₃ ; ##STR5## (c) CO₂ H; (d) CH(R₆)CO₂ H,

(e) a moiety of the formula: ##STR6## wherein R₁, R₂ and R₃ areindependently hydrogen, C₁ -C₆ alkyl or t-butoxycarbonyl;

R₄ and R₅ are independently t-butoxycarbonyl or hydrogen;

R₆ is hydrogen or hydroxy;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

Most preferred are those compounds of formula 1 wherein:

the moiety Q is a fused phenyl;

Z₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy,amino, nitro, sulfonylamino or trifluoromethyl;

Z₂ is hydrogen or, where Z₁ is a halogen, Z₂ is also a halogen;

X is oxygen;

A is C₁ -C₅ alkyl, CH₂ phenyl, CH₂ thienyl, CH₂ pyridyl, CH₂ furyl, orethyl piperidine; wherein said phenyl, thienyl, pyridyl, furyl orpiperidine moiety is optionally substituted with (C₁ -C₆)alkyl, benzyl,oxybenzyl phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino,carboxyl or carbomethoxy;

n is an integer from 0-3;

Y is a moiety selected from:

(a) NHR₁ R₂, N⁺ R₁ R₂ R₃ ; ##STR7## (c) CO₂ H; (d) CH(R₆)CO₂ H,

(e) a moiety of the formula: ##STR8## wherein R₁, R₂ and R₃ areindependently hydrogen, C₁ -C₆ alkyl or t-butoxycarbonyl;

R₄ and R₅ are independently t-butoxycarbonyl or hydrogen;

R₆ is hydrogen or hydroxy;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

In another aspect of the present invention, certain novel intermediatesuseful in the preparation of the final compounds are contemplated. Thusthe invention encompasses intermediates of the following formula:##STR9## wherein the Q moiety is phenyl or pyridyl and Z₁ is hydrogen,halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy, amino, nitro,sulfonylamino or trifluoromethyl; and

Z₂ is hydrogen or a halogen.

Also included are intermediates of the general formula: ##STR10##wherein the Q moiety is phenyl or pyridyl and Z₁ is hydrogen, halogen,C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy, amino, nitro,sulfonylamino or trifluoromethyl;

Z₂ is hydrogen or a halogen, A is C₁ -C₆ alkylaryl or C₁ -C₆alkylheterocyclyl,

wherein aryl is biphenyl, naphthyl or phenyl; and heterocyclyl is a 5 or6 membered saturated or unsaturated heterocyclic group containing 1-4nitrogen atoms, an oxygen or a sulfur atom; wherein said aryl orheterocyclyl group is optionally substituted with (C₁ -C₆)alkyl, benzyl,oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro, amino,carboxyl, carbo(C₁ -C₄)alkoxy or methylsulfonylamino;

and R₈ is hydrogen or a hydroxy protecting group. A suitable hydroxyprotecting group includes any conventional protecting groups for hydroxymoieties as routinely used by those skilled in the art such as thosefound in T. Greene, "Protecting Groups in Organic Synthesis", J. Wileyand Sons, 1981. These include silyl esters, aliphatic esters andaromatic esters such as trimethylsilyl, t-butyldimethylsilyl, acetyl,benzoyl and the like.

The compounds of the present invention are prepared in accordance withthe methods described below and illustrated in the following Schemes.The first step in the synthesis involves a novel addition, cyclizationreaction of the α-bromo-γ-butyrolactone shown in Scheme 1 with asuitably substituted 2-nitro or 2-aminophenol. The reaction may becarried out in two discrete steps, beginning with known, generallycommercially available nitrophenols having most of the definitions for Zcited in the invention description. The solvent is usually DMF and abasic reagent such as K₂ CO₃ is needed to drive the reaction tocompletion. The cyclization step occurs upon reduction of the nitrogroup with any of the reagent systems known to be useful for thisreduction, including palladium catalyzed hydrogenation, nickel andsodium borohydride, and iron-acetic acid. Alternatively, especially incases where Z is a nitro group or Q is a fused pyridyl, both theaddition and cyclization steps may be carried out in a single procedureusing a base, such as K₂ CO₃ or NaH, in DMF with or without heating.

Having generated the benzoxazine heterocyclic ring system in thismanner, the intermediate alcohol 2 may be prepared by a three stepsequence of reactions. Protection of the alcohol group, with a knownprotecting group such as a t-butyldimethylsilyl derivative orequivalents thereof, is followed by reaction at the 4-position involvingnucleophilic displacement of an alkyl or aryl halide under basicconditions: for example, NaH in DMF is highly effective. Alternatively,derivatization of the 4-position nitrogen may be carried out byMitsunobu reaction of a suitably substituted alcohol. Deprotection ofthe alcohol with any of the usual fluoride anion reagents or underacidic conditions provides compound 2.

As is apparent, Scheme 1 depicts the preparation of benzoxazinecompounds wherein the "Q" moiety is a fused phenyl. The pyrido-oxazinecompounds where the "Q" moiety is a fused pyridyl may be prepared inaccordance with the same procedure by substituting a suitablysubstituted 2-nitro- or 2-amino pyridoxyl moiety for the phenol startingmaterial depicted in Scheme 1. In the remaining synthesis depicted inSchemes 2-10 hereinafter, the pyrido-oxazine compounds may likewise beconveniently substituted for the benzoxazine compounds illustrated inthe Schemes. ##STR11##

The key step of the synthesis is a coupling reaction of the alcohol 2with a substituted phenol, by Mitsunobu reaction, as shown in Scheme 2.The Mitsunobu reaction may be one of several variants known in the art;the selection of the appropriate phosphine, azodicarbonyl reagent, andsolvent will be at the discretion of the practitioner, based onpublished precedents and on empirical results with the particularcombination of substrates to be coupled. Guidance can be found in thereview article by D. L. Hughes, in Organic Reactions, 42, 335-656(1992), and in the detailed examples below. In most casestriphenylphosphine (Ph₃ P) and diethylazodicarboxylate (DEAD), oralternatively tributylphosphine (BU₃ P) and (azodicarbonyl)dipiperidine(ADDP), will suffice.

At the time of the Mitsunobu reaction, the group Y will in most caseshave to be in a protected form of a more potent compound, or else (forinstance when the desired compound is a heterocycle) Y will be aprecursor functional group convertible into the desired heterocycle.Once the linkage of the two portions has been established, the group Yis converted, if necessary, into the preferred functional group, asshown in the Schemes below. Suitable protecting groups for guanidinesand amines include, but are not limited to, trifluoroacetyl,t-butoxycarbonyl (Boc), and benzyloxycarbonyl. Suitable protectinggroups for carboxylic acids include, but are not limited to, lower alkylesters or benzyl esters; suitable precursor groups include olefin,nitrile, or oxazolidine. The chemical processes presented in the Schemeare in general applicable to all definitions of Y. ##STR12##

To obtain those compounds where X=hydrogen, the Mitsunobu couplingreaction is carried out on a reduced derivative of compound 2. Thereduction is most easily carried out on the protected precursor of 2 asillustrated in Scheme 3 by using a commercially available borane reagentsuch as borane-THF complex. After reduction, deprotection as shown inScheme 1 affords the alcohol which undergoes the Mitsunobu reaction asbefore. ##STR13##

In Scheme 4, reaction of 2-(4-hydroxyphenyl)ethylamine withdi-t-butyldicarbonate, to afford a protected phenolic coupling componentfor the Mitsunobu reaction, is illustrated. A variety of(hydroxyphenyl)alkylamines are commercially available or are knowncompounds; they can be synthesized by common methods such as reductiveamination of benzaldehydes, hydrogenation of arylacetonitriles oraryloxyacetonitriles, reduction of cinnamides or cinnamylamines, etc.Methods for their preparation can be chosen from, but are not limitedto, the examples presented herein.

Also in Scheme 4, the generation of a protected guanidine from thecorresponding amine is illustrated, again providing a phenolic componentfor the Mitsunobu coupling. The illustrated use ofN,N'-bis(t-butoxy-carbonyl)-S-methylisothiourea for this purpose is aknown procedure (R. J. Bergeron, J. S. McManis, J. Org. Chem., 52,1700-1703 (1987); it is in some cases improved by the addition of silveracetate to the reaction mixture. (See also M. S. Bernatowicz, Y. Wu, G.R. Matsueda, Tetrahedron Letters, 34, 3389 (1993)). These methods are ingeneral applicable to all amines with the various definitions of Ar, X,W, and n.

Alternatively, one can prepare 1 (see description of invention) withY=NH₂ and then convert the amino group into a guanidino group by theabove or by other known methods (e.g., M. S. Bernatowicz, Y. Wu, G. R.Matsueda, J. Org. Chem., 57, 2497-2502 (1992) and references therein).##STR14##

For compounds where Y is a carboxylic acid (see definition), thestarting phenols with the appropriate substitution are known compoundsand are commercially available as either the carboxylic acids or thecorresponding alkanoic esters. The acids are first protected as thealkanoic esters prior to Mitsunobu coupling in the usual manner as shownin Scheme 5. After coupling, saponification with NaOH provides the finalproducts. ##STR15##

Where n is 0 and Y is CHO (Scheme 6), reaction with bromoform and KOHfollowed by methylation of the crude product provides hydroxy ester 3.Hydrolysis of the ester thus formed, affords the corresponding hydroxyacid 4. The acid 4, may be treated with reagents such as thionylchloride to generate the chloro derivative, followed by reaction withthiourea to produce the thiazolidinedione also shown in Scheme 6.##STR16##

For compounds where Y is, in effect, a protected amine or guanidine(Scheme 7), reaction under acidic conditions, for example,trifluoroacetic acid or hydrochloric acid in isopropanol, affords theamine and guanidine salts, respectively. ##STR17##

In the cases where A (see description of invention), is a carboxylicacid substituted benzyl group, the alcohol shown in Scheme 8 may beprepared by the method outlined in Scheme 1, using known benzylichalides bearing a carboxylic ester substituent. The previously describedtransformations are carried out with the ester in place, followed byhydrolysis of the ester to generate the acid, usually in the final stepof the sequence. ##STR18##

The transformations outlined in Scheme 1, for preparation of alcohol 2and the coupling reaction described in Scheme 2 may be carried out onnitro substituted starting materials to afford the products shown inScheme 9. Reduction of the nitro group with reagents such as iron/aceticacid or palladium catalyzed hydrogenation, can be carried out on, forexample, compounds originating from the protected amino or guanidinophenols shown in Scheme 2. Alternatively, the reduction may be effectedon the unprotected compounds, provided that no further manipulations areneeded. With the protected species, the resulting amine may be furtherfunctionalized with electrophilic reagents to afford the products shownin Scheme 9. Similar transformations can be carried out on compoundsderived from 2 bearing a nitrobenzyl substituent, as shown in Scheme 10.##STR19##

The foregoing reactions are performed in a solvent appropriate to thereagents and materials employed and suitable for the transformationbeing effected. It is understood by those skilled in the art of organicsynthesis that the various functionalities present on the molecule mustbe consistent with the chemical transformations proposed. This willfrequently necessitate judgment as to the order of synthetic steps,protection of reactive groups, and selection of reaction conditions.Reaction conditions compatible with the substituents employed will beapparent to one skilled in the art, as will be the selection ofprotecting groups where needed.

From formula 1 it is evident that some of the compounds of the inventionmay have one or more asymmetrical carbon atoms in their structure. It isintended that the present invention include within its scope thestereochemically pure isomeric forms of the compounds as well as theirracemates. Stereochemically pure isomeric forms may be obtained by theapplication of art known principles. Diastereoisomers may be separatedby physical separation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Suitable pharmaceutical salts are those of inorganic or organic acids,such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, phosphoric acid, acetic acid, succinic acid, oxalicacid, malic acid and the like. Suitable salts are also those ofinorganic or organic bases, such as KOH, NaOH, Ca(OH)₂, Al(OH)₃,piperidine, morpholine, ethylamine, triethylamine and the like.

Also included within the scope of the invention are the hydrated formsof the compounds which contain various amounts of water, for instance,the hydrate, hemihydrate and sesquihydrate forms.

The ability of bacteria to quickly respond to changes in the environmentis of utmost importance for their survival. Bacteria are capable ofrapidly responding and adapting to such diverse stimuli as changes innutrients, osmolarity, temperature, light, or host environment. Theseresponses may be transient, such as those required for changes inmotility or for entry into a host cell. Alternatively, the responses mayrequire major shifts in gene expression and cell morphology, such asthose required for sporulation, or for survival within a macrophage. Themechanism by which bacteria are able to sense cues from the physicalenvironment (or from within the cytoplasm) and process these signalsinto appropriate responses often involves the so-called "two-component"systems.

As stated above, the treatment method of the present invention is basedon the inhibition of this "two-component switch" system. All bacteriause this mechanism to control various adaptive/virulence factors tofacilitate establishment of a bacterial population in the environment(for example, a bacterial infection in a host). The system invariablyconsists of a sensor which either activates a kinase or is a part of thekinase, and which upon stimulation, autophosphorylates. Thisphosphorylated species is a highly active phosphodonor which immediatelytransfers its phosphate to a "regulatory" component, which in turninitiates the biological response such as transcription or furtherphosphotransfer in a cascade which eventually ends in regulation ofbacterial gene expression. Although each of the kinases and responseregulators has a unique sequence (in fact, even functionally identicalproteins have slightly different sequences in different species) theyshare a homologous biochemical mechanism and they share significanthomology in the active site.

As stated, the present invention provides compounds which exhibitantibiotic activity by inhibiting the autophosphorylation of bacterialhistidine kinases. They also inhibit the transfer of phosphate fromphosphorylated histidine kinases to the aspartyl residues of thephosphate acceptor proteins involved in regulation of bacterial geneexpression.

This invention further provides a method of treating bacterialinfections, or enhancing or potentiating the activity of otherantibacterial agents, in warm-blooded animals, which comprisesadministering to the animals a compound of the invention alone or inadmixture with another antibacterial agent in the form of a medicamentaccording to the invention.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents, and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing for example, from about 0.5% to 5% of suspendingagent, syrups containing, for example, from about 10% to 50% of sugar,and elixirs containing, for example, from about 20% to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5% to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

Compositions for topical application may take the form of liquids,creams or gels, containing a therapeutically effective concentration ofa compound of the invention admixed with a dermatologically acceptablecarrier.

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Solid carriers include starch,lactose, dicalcium phosphate, microcrystalline cellulose, sucrose andkaolin, while liquid carriers include sterile water, polyethyleneglycols, non-ionic surfactants and edible oils such as corn, peanut andsesame oils, as are appropriate to the nature of the active ingredientand the particular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, for example, vitamin E, ascorbicacid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacological acceptable salt can be prepared in watersuitably mixed with a surfactant such as hydroxypropyl-cellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.1 mg/kg to about 400mg/kg of animal body weight, preferably given in divided doses two tofour times a day, or in sustained release form. For most large mammalsthe total daily dosage is from about 0.07 g to 7.0 g, preferably fromabout 100 mg to 1000 mg. Dosage forms suitable for internal use comprisefrom about 100 mg to 500 mg of the active compound in intimate admixturewith a solid or liquid pharmaceutically acceptable carrier. This dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

The production of the above-mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredients(s) with the diluent(s) to form apharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

The compounds of the present invention have antibacterial activity asdetermined by the following tests. First, the compounds were tested fortheir activity in inhibiting the autophosphorylation of Kinase A and thetransphosphorylation of Spo0F, two proteins involved in one of the abovedescribed signal transduction systems controlling gene expression inbacteria. Representative compounds were then tested for antibacterialactivity against selected organisms by the standard MIC method. Theresults are set forth below.

Table 1 lists examples of compounds of the invention, along with theirIC₅₀ values in the HPK in vitro assay described below, and MIC valueranges for the selected microorganisms identified below. These examplesare merely illustrative of the invention, and are not intended to limitthe scope of the claims in any way. In Table 1, benzoxazine compoundsare listed in accordance with the following formula: ##STR20##

                                      TABLE 1                                     __________________________________________________________________________    Cpd #                                                                             A       Z    X  pos.(n)-Y                                                                            IC.sub.50                                                                         MIC.sub.(G+/G·)                       __________________________________________________________________________     1  3-Cl-Bz H    O  4(1)-T-Boc                                                                           253                                                 2  3-Cl-Bz H    O  4(1)-T  55 8-32/32->128                                    3  4-Cl-Bz H    O  4(1)-T-Boc                                                                           283                                                 4  4-Cl-Bz H    O  4(1)-T  47 8-16/8->128                                     6  4-Cl-Bz H    O  4(2)-T  61 1-2/2-64                                        7  4-Cl-Bz H    O  3(2)-T-Boc                                                                           308                                                 8  4-Cl-Bz H    O  3(2)-T  89 8-16/8->128                                    10  4-Cl-Bz H    O  3(1)-T 122                                                12  2-Cl-Bz H    O  3(1)-T 140                                                13  2-Cl-Bz H    O  4(1)-T-Boc                                                                           272                                                14  2-Cl-Bz H    O  4(1)-T 172                                                15  2-Cl-Bz H    O  3(2)-T-Boc                                                                           165                                                16  2-Cl-Bz H    O  3(2)-T  74 8-16/8->128                                    17  2-Cl-Bz H    O  4(2)-T-Boc                                                                           352                                                18  2-Cl-Bz H    O  4(2)-T 264                                                19  2-Cl-Bz H    O  4(1)-G  16 1-4/4->128                                     20  2-Cl-Bz H    O  4(2)-G  16                                                21  4-Cl-Bz H    O  4(1)-G  26                                                22  4-Cl-Bz H    H,H                                                                              4(2)-G  41 2-4/8->64                                      23  3-Cl-Bz H    H,H                                                                              4(2)-G  17 1-2/4->128                                     24  3-Cl-Bz 6-Me O  4(2)-G  56                                                25  2-Cl-Bz H    H,H                                                                              4(1)-G  23 1-2/8->64                                      26  4-Cl-Bz H    O  4(2)-G  68 2-4/4->128                                     27  Bz      H    O  4(2)-G-diBoc                                                                         340                                                28  Bz      H    O  4(2)-G  44                                                29  2-OMe-Bz                                                                              H    O  4(2)-G  54                                                31  3-F-Bz  H    O  4(2)-G  46                                                33  3-OMe-Bz                                                                              H    O  4(2)-G 145                                                35  3-BOB   H    O  4(2)-G  24                                                36  3-OH-Bz H    O  4(2)-G  72                                                37  4-OMe-Bz                                                                              H    O  4(2)-G  51                                                38  4-PBz   H    O  4(2)-G  34                                                39  3,5-diCl-Bz                                                                           H    O  4(1)-T  46 4-16/4->128                                    40  315-diCl-Bz                                                                           H    O  4(2)-G  24 2/8->128                                       42  4-pyrMe H    O  4(2)-G 444                                                43  1-napMe H    O  4(2)-G  13                                                45  2-napMe H    O  4(2)-G  17                                                46  Thi     H    O  4(2)-G  68                                                47  4-Cl-Thi                                                                              H    O  4(2)-G-diBoc                                                                         398                                                48  4-Cl-Thi                                                                              H    O  4(2)-G  26                                                50  3-Cl-Bz 6-Cl O  4(2)-G  9  2/4->128                                       52  3-Cl-Bz 6-Ph O  4(2)-G  36                                                53  3-Cl-Bz 7-CF.sub.3                                                                         O  4(2)-G-diBoc                                                                          84                                                54  3-Cl-Bz 7-CF.sub.3                                                                         O  4(2)-G  14                                                55  3-Cl-Bz 7-F  O  4(2)-G  28                                                57  3-Cl-Bz 6,8-diCl                                                                           O  4(2)-G  17                                                58  3-Cl-Bz 7-Me O  4(2)-G  17 2/4->128                                       59  Me      H    O  4(2)-G-diBoc                                                                         473                                                60  Me      H    O  4(2)-G  55 16-34/16->64                                   61  n-pentyl                                                                              H    O  4(2)-G  41 4-8/4-64                                       64  3,5-diCl-Bz                                                                           H    O  3(2)-T  32 4-8/4->128                                     66  4-Me-Bz H    H,H                                                                              4(2)-G  19                                                68  2,4-diCl-Bz                                                                           H    H,H                                                                              4(2)-G  17                                                69  3-Cl-Bz H    O  3(2)-T-Boc                                                                           358                                                70  3-Cl-Bz H    O  3(2)-T  65 8-16/8->128                                    71  3-Cl-Bz H    O  4(2)-G-diBoc                                                                         300                                                72  3-Cl-Bz H    O  4(2)-G  30 2-414->128                                     73  3-Cl-Bz H    O  3(1)-T-Boc                                                                           354                                                74  3-Cl-Bz H    O  3(1)-T  81 8-16/16->128                                   76  3-Cl-Bz H    O  4(3)-T  32 8/8->128                                       77  3-Cl-Bz H    O  4(1)-G-diBoc                                                                          51                                                78  3-Cl-Bz H    O  4(1)-G  32 1-4/4->128                                     79  3-Cl-Bz H    O  4(2)-T  78 8-16/8->128                                    80  3-Cl-Bz 7-NO.sub.2                                                                         O  4(2)-G-diBoc                                                                         162                                                82  3-Cl-Bz 7-NO.sub.2                                                                         O  4(2)-T  27                                                84  3-Cl-Bz 7-NO.sub.2                                                                         O  4(2)-G  30                                                87  2-Cl-Bz 7-NO.sub.2                                                                         O  4(1)-G  11                                                89  2-Cl-Bz 6-NO.sub.2                                                                         O  4(2)-G  17 1-4/2->128                                     91  3-NO.sub.2 -Bz                                                                        7-NO.sub.2                                                                         O  4(2)-G  33                                                92  3-Cl-Bz 6-A  O  4(2)-G  34 2-16/4->128                                    95  3-NO.sub.2 -Bz                                                                        H    O  4(2)-G  32                                                97  4-NO.sub.2 -Bz                                                                        7-NO.sub.2                                                                         O  4(2)-G  53                                                99  3-NO.sub.2 -Bz                                                                        7-OMe                                                                              O  4(2)-G-diBoc                                                                         343                                                100 3-NO.sub.2 -Bz                                                                        7-OMe                                                                              O  4(2)-G  32                                                104 4-CO.sub.2 Me-B                                                                       H    O  4(2)-T  24                                                106 3-CO.sub.2 Me-B                                                                       H    O  4(2)-T 166                                                110 4-CO.sub.2 H-Bz                                                                       H    O  4(2)-T 324                                                111 3-CO.sub.2 H-Bz                                                                       H    O  4(2)-T-Boc                                                                           113                                                112 3-CO.sub.2 H-Bz                                                                       H    O  4(2)-T 254                                                127 3-Cl-Bz H    O  3(2)-CO.sub.2 H                                                                      251                                                134 3-Cl-Bz H    O  4(0)-Thia                                                                             23                                                139 4-NO.sub.2 -Bz                                                                        H    O  4(2)-G  24                                                140 4-OMe-Bz                                                                              H    O  4(2)-G-diBoc                                                                         343                                                141 2,4-diCl-Bz                                                                           H    O  4(2)-G  37                                                142 4-Cl-Bz H    O  3(3)-T  42                                                143 2-NO.sub.2 -Bz                                                                        7-NO.sub.2                                                                         O  4(2)-G-diBoc                                                                          73                                                144 3-Cl-Bz H    O  4(2)-T-Boc                                                                           348                                                __________________________________________________________________________     KEY:                                                                          Bz = benzyl                                                                   T = NH.sub.2                                                                  G = NHC(NH)NH.sub.2                                                           napMe = naphthylmethyl                                                        pyrMe = pyridylmethyl                                                         ClThi = 2Chloro-4-thienylmethyl                                               Thi = thienylmethyl                                                           BoB = benzyloxybenzyl                                                         PBz = phenylbenzyl                                                            Thia = 2,4 dioxodihydrothiazole                                          

In Table 2, activities for pyrido-oxazine compounds of the followingformula where Q is a fused pyridyl moiety are listed: ##STR21##

                  TABLE 2                                                         ______________________________________                                        Cpd #  A       Z.sub.1 Z.sub.2                                                                        X   pos.(n)-Y                                                                              IC.sub.50                                                                          MIC.sub.(G+/G·)            ______________________________________                                        25     3-Cl-Bz H,H      O   4(2)-G    41                                      62     3-Cl-Bz H,H      O   4(2)-G   174                                      ______________________________________                                         KEY:                                                                          Bz = benzyl                                                                   T = NH.sub.2                                                                  G = NHC(NH)NH.sub.2                                                           napMe = naphthylmethyl                                                        pyrMe = pyridylmethyl                                                         ClThi = 2Chloro-4-thienylmethyl                                               Thi = thienylmethyl                                                           BoB = benzyloxybenzyl                                                         PBz = phenylbenzyl                                                            Thia = 2,4 dioxodihydrothiazole                                          

The protocols for the above referenced assays are as follows.

1. Autophosphorylation of Kinase A and Transphosphorylation of Spo0FAssay

To study the effect of the compounds of the present invention on thesignal transduction process in bacteria, the inhibiting effect of thecompounds on the sporulation operon proteins Kinase A and Spo0F wasexamined. Specifically, the inhibition of autophosphorylation of KinaseA and the transphosphorylation of Spo0F was determined in the followingassays. The Spo0F response regulator is the primary substrate forphosphorylation by the protein kinase, Kin A, involved in thesporulation process in bacteria. See D. Burbulys, K. A. Trach, J. A.Hoch, Cell, 64, 545-552 (1991). Spo0F and KinA were prepared fromrecombinant E. coli overexpressing the proteins (J. Cavanagh et al,Amino Acids, 6, 131-140 (1994) and references therein).

The following stock reagents were either prepared and used promptly orstored at the indicated temperature:

8× Salts: 2M KCl (5 mL), 1M MgCl₂ (800 mL), 1M CaCl₂ (100 mL), 10 mg/mLphenylmethylsulfonyl fluoride (200 mL), 1M dithioreitol (50 mL), 0.25MNa₂ EDTA (32 mL) and H₂ O 3.82 mL (-20° C.)

5× Loading Dye: 0.5M TRIS-HCl-pH 6.8 (7.5 mL), 10% SDS (2 mL) 0.1%bromophenol blue (0.5 mL), 100% glycerol (3 mL) and 12.5M2-mercaptoethanol (0.3 mL)

1-1.3 mg/mL KinA:15 mM TRIS-HCl, pH 8.0, 6 mM KCl; 4 mM2-mercaptoethanol; 40% glycerol (-20° C.)

1 mg/mL Spo0F: 17.5 mM TRIS-HCl, pH 8.0; 0.7 mM KCl; 0.7 mM MgCl₂ ; 0.7mM CaCl₂ ; 5 mM 2-mercaptoethanol; 30% Glycerol (-20° C.)

5% Stacking Gel: 40% 29:1 acrylamide:bis acrylamide (1.25 mL), 0.5MTRIS-HCl, pH 6.8 (2.5 mL), 10% SDS (0.1 mL), D-H₂ O (6.15 mL) 10%ammonium persulfate (100 mL) and TEMED (25 mL)

SDS Running Buffer: TRIS-BASE (3.02 g), glycine (14.4 g) SDS (1 g), D-H₂O (to 1 L)

The reaction mixture was prepared from 8× Salts (87 μL), 1M TRIS, pH 8(118 μL), 50% glycerol (63 μL), Spo0F (14.1 μL) and KinA (7.0 μL).Microcentrifuge tubes were charged with the reaction mixture (18.5 μL)and a 1.0 mM solution of the test compound in 5% DMSO (18.5 μL), andincubated for 15 min on ice. 100 mM ATP solution (3.0 μl, containing 625μCi ³² P!ATP) was added, and the mixture left for 10 minutes at roomtemperature. The reaction was quenched with 5× loading dye (10 μL pertube) and the samples were loaded on a prepared 5% Stacking Gel, orstored on dry ice until ready for use. The prepared wells were filledwith SDS Running Buffer, samples were loaded into the wells, and 80volts were applied to the gel until the dye front reached the bottom ofthe stacking gel. The voltage was then increased to 250 volts untilelectrophoresis was complete. Radioactive bands in the gel correspondingto phosphorylated KinA and Spo0F were imaged and quantitated with aphosphoimager.

If either enzyme was inhibited (as evidenced by the absence of labelledprotein in the developed gel), an IC₅₀ was calculated by running theassay with a range of inhibitor concentrations from 1 to 500 μM. Afterelectrophoresis of the reaction mixtures, percent inhibition wasdetermined by measuring the concentration of radioactive phosphorus witha phosphoimager and calculating the values using a software program(BioRad Molecular Analyst). IC₅₀ values of less than 500 μM areconsidered active.

2. MIC Anitimicrobial Assay

The in vitro antimicrobial activity of the compounds was determined bythe microdilution broth method following the test method from theNational Committee for Laboratory Standards (NCCLS). This method isdescribed in the NCCLS Document M7-A2, Vol.10, No.8 "Methods forDilution Antimicrobial Susceptibility Test for Bacteria that GrowAerobically--Second Edition."

In this method two-fold serial dilutions of drug in cation supplementedMueller-Hinton broth are added to wells in microdilution trays. The testorganisms are prepared by adjusting the turbidity of actively growingbroth cultures so that the final concentration of test organism after itis added to the wells is approximately 5×10⁴ CFUs/well.

Following inoculation of the microdilution trays, the trays areincubated at 35° C. for 16-20 hours and then read. The MIC is the lowestconcentration of test compound that completely inhibits growth of thetest organism. The amount of growth in the wells containing the testcompound is compared with the amount of growth in the growth-controlwells (no test compound) used in each tray. As set forth in Tables 1 and2, compounds of the present invention were tested against a variety ofGram+ and Gram- pathogenic bacteria resulting in a range of activities,from 1→128 μg/mL depending on the organism tested. The following testorganisms were utilized in the assay:

gram positive bacteria

Enterococcus faecalis ATCC 29212

Enterococcus faecalis oc 3041

Enterococcus faecium oc 2993

Methicillin resistant Staphylococcus aureus oc 2089

Methicillin resistant Staphylococcus aureus oc667

Staphylococcus aureus ATCC 29213

Staphylococcus aureus ATCC 6538

Staphylococcus epidermidis oc 2603

Gram negative bacteria

Escherichia coli oc 2605

Escherichia coli oc 2530 ss

Klebsiella pneumoniae oc 1943

Pseudomonas aeroginosa oc 161

Pseudomonas aeroginosa ATCC 27853

The following examples describe in detail the chemical synthesis ofrepresentative compounds of the present invention. The procedures areillustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

Methods of preparing the exemplified compounds of the invention arepresented below. These examples are intended to illustrate the methodsof synthesis, and are not intended to limit the scope of the claims inany way. Abbreviations used: DEAD, diethyl azodicarboxylate; Ph₃ P,triphenylphosphine; Bu₃ P, tri-n-butylphosphine; THF, tetrahydrofuran;DMF, N,N-dimethylformamide; ADDP, 1,1'-(azodicarbonyl)dipiperidine.

REFERENCE EXAMPLE 1 Intermediate 9086-181-1Dihydro-3-(2-nitrophenoxy)-2-(3H)-furanone

Method A

2-nitrophenol (20.2 g, 1 eq) was dissolved in DMF (250 ml) and treatedwith K₂ CO₃ (30 g, 1.3 eq), followed by addition ofα-bromo-γ-butyrolactone (14.4 ml, 1.2 eq) at room temperature undernitrogen. After stirring 18 h, an additional amount of K₂ CO₃ (5 g, 0.25eq) was added. After a total reaction time of 48 h, the reaction wascooled in an ice bath and acetic acid (13.7 ml, 1.65 eq) was added. Thecrude reaction mixture was poured into water and extracted with EtOAc.The combined extract was concentrated under vacuum and crystallized fromethanol/water to afford white needles (22.4 g 70% yield), mp 112°-113°C.; IR (KBr) 2939, 1771, 1607, 1586, 1524, 1481, 1356, 1275, 1221, 1194,1019, 745 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.84 (dd, J=8.1, 1.6 Hz, 1H),7.62-7.48 (m, 2H), 7.16 (m, 1H), 5.02 (apparent t, J=7.4 Hz, 1H),4.62-4.52 (m, 1H), 4.45-4.35 (m, 1H), 2.83-2.55 (m, 3H). Anal. Calc'dfor C₁₀ H₉ NO₅ : C 53.82, H 4.06, N 6.28. Found: C 53.65, H 3.84, N6.05.

REFERENCE EXAMPLE 2 Intermediate 10353-186-ADihydro-3-(4-methyl-2-nitrophenoxy)-2-(3H)-furanone

Prepared from 4-methyl-2-nitrophenol by method A in 33% yield as a whitesolid, MS (Cl) 238 (MH⁺); IR (KBr) 3523, 3072, 3005, 1770, 1623, 1577,1530, 1496, 1463, 1392, 1357, 1282, 1270, 1225, 1194, 1184, 1095, 1020,992, 804 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.66 (s, 1H), 7.38 (m, 2H), 4.93(apparent t, J=7.4 Hz, 1H), 4.59 (m, 1H), 4.39 (apparent q, J=7.3 Hz,1H), 2.78-2.61 (m, 2H), 2.38 (s, 3H). Anal. Calc'd for C₁₁ H₁₁ NO₅ : C55.70 H 4.67, N 5.90. Found: C 55.62, H 4.66, N 5.82.

REFERENCE EXAMPLE 3 Intermediate 12168-2-1Dihydro-3-(4-methoxy-2-nitrophenoxy)-2-(3H)-furanone

Prepared from 4-methoxy-2-nitrophenol by method A to afford yellowneedles in 52% yield, MS (Cl) 254 (MH⁺); IR (KBr) 3519, 3102, 3023,2984, 1765, 1726, 1581, 1532, 1496, 1463, 1442, 1274, 1265, 1229, 1218,1178, 1145, 1092, 1068, 1018, 992, 942, 859, 839, 806, 791, 755 cm⁻¹ ; ¹H NMR (CDCl₃) δ 7.52 (d, J=9.1 Hz, 1H), 7.39, (d, J=3.1 Hz, 1H), 7.31(dd, J=9.1, 3.0 Hz, 1H), 4.87 (apparent t, J=7.5 Hz, 1H), 4.55 (m, 1H),4.36 (m, 1H), 3.87 (s, 3H), 2.82-2.69 (m, 1H), 2.68-2.53 (m, 1H). Anal.Calc'd for C₁₁ H₁₁ NO₆ : C 52.18, H 4.38, N 5.53. Found: C 52.19, H4.50, N 5.43.

REFERENCE EXAMPLE 4 Intermediate 11653-187Dihydro-3-(5-methoxy-2-nitrophenoxy)-2-(3H)-furanone

Prepared from 5-methoxy-2-nitrophenol by method A in 53% yield, mp109°-110° C.; MS (Cl) MH⁺ 254; IR (KBr) 3517, 3100, 3075, 2994, 2955,2931, 2852, 1484, 1258, 1079, 714 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.98 (d,1H, J=9.1 Hz), 7.02 (d, 1H, J=2.5 Hz), 6.76 (dd, 1H, J=2.5, 9.2 Hz),5.62 (t, 1H, J=8.7 Hz), 4.48 (dt, 1H, J=2.4, 8.8 Hz), 4.28 (m, 1H), 3.88(s, 3H), 2.89-2.73 (m, 1H), 2.38-2.29 (m, 1H). Anal. Calc'd for C₁₁ H₁₁NO₆ : C 52.18, H 4.38, N 5.53. Found: C 51.97, H 4.18, N 5.45.

REFERENCE EXAMPLE 5 Intermediate 11578-25Dihydro-3-(3-methyl-2-nitrophenoxy)-2(3H)-furanone

Prepared from 3-methyl-2-nitrophenol by method A in 41% yield. A portionof this material was crystallized from CH₂ Cl₂ /ether to afford a whitesolid, mp 82°-84° C.; IR (KBr) 2946, 1792, 1530, 1294, 1275, 1182, 1118,1014, 994, 777, 638 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.32 (s, 3H), 2.45-2.57 (m,1H), 2.63-274 (m, 1H), 4.32-4.40 (m, 1H), 4.48-4.55 (m, 1H), 4.96 (t,J=7.4 Hz, 1H), 6.97 (dd, J=7.1, 0.6 Hz, 1H), 7.24-7.36 (m, 2H); MH⁺ atm/z=238; Anal. Calc'd for C₁₁ H₁₁ NO₅ : C, 55.70; H, 4.67; N, 5.90.Found: C, 55.61; H, 4.62; N, 5.87.

REFERENCE EXAMPLE 6 Intermediate 11578-61Dihydro-3-(4-chloro-2-nitrophenoxy)-2(3H)-furanone

Prepared from 4-chloro-2-nitrophenol by Method A in 60% yield andisolated as a yellow solid, mp 136°-140° C.; IR (KBr) 3110, 1786, 1771,1608, 1527, 1488, 1359, 1276, 1193, 1180, 1020, 825, 734 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.57-2.83 (m, 2H), 4.35-4.45 (m, 1H), 4.54-4.63 (m, 1H), 4.98(t, J=7.4 Hz, 1H), 7.48-7.56 (m, 2H), 7.85 (d, J=2.3 Hz, 1H); MH⁺ atm/z=258; Anal. Calc'd for C₁₀ H₈ ClNO₅ : C, 46.62; H, 3.13; N, 5.44.Found: C, 46.61; H, 3.11; N, 5.20.

REFERENCE EXAMPLE 7 Intermediate 11578-62Dihydro-3-(4-carbomethoxy-2-nitrophenoxy)-2(3H)-furanone

Prepared from 4-carbomethoxy-2-nitrophenol by Method A in 30% yieldusing equal portions of reagents. This material was isolated directlyfrom the aqueous workup as a beige solid, mp 99°-101° C.; IR (KBr) 2958,1780, 1726, 1618, 1531, 1348, 1300, 1270, 1179, 1127, 756 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.62-2.85 (m, 2H), 3.95 (s, 3H), 4.44 (dt, J=9.3, 7.2 Hz, 1H),4.58-4.65 (m, 1H), 5.14 (t, J=7.3 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 8.24(dd, J=8.8, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H); MH⁺ at m/z=282; Anal.Calc'd for C₁₂ H₁₁ NO₇.0.3H₂ O: C, 50.29; H, 4.08; N, 4.89. Found: C,50.03; H, 3.85; N, 4.68.

REFERENCE EXAMPLE 8 Intermediate 11578-32Dihydro-3-(4-phenyl-2-nitrophenoxy)-2(3H)-furanone

Prepared from 4-benzyl-2-nitrophenol by Method A in 54% yield as ayellow crystalline solid, mp 117°-119° C.; IR (KBr) 2931, 1785, 1625,1535, 1346, 1334, 1279, 1261, 1156, 1022, 756 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.64-2.85 (m, 2H), 4.42 (q, J=7.3 Hz, 1H), 4.57-4.65 (m, 1H), 5.05 (t,J=7.3 Hz, 1H), 7.40-7.59 (m, 6H), 7.78 (dd, J=8.7, 2.4 Hz, 1H), 8.07 (d,J=2.4 Hz, 1H); Anal. Calc'd for C₁₆ H₁₃ NO₅ : C, 64.21; H, 4.38; N,4.68. Found: C, 64.00; H, 4.20; N, 4.59.

REFERENCE EXAMPLE 9 Intermediate 11578-50Dihydro-3-(4-trifluoromethyl-2-nitrophenoxy)-2(3H)-furanone

Prepared from 4-trifluoromethyl-2-nitrophenol by Method A in 51% yieldusing equal portions of reagents. This material was isolated as a whitesolid, mp 128°-129° C.; IR (KBr) 3100, 2995, 1782, 1626, 1537, 1358,1329, 1283, 1159, 1131, 1098, 998, 822 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.63-2.86 (m, 2H), 4.40-4.48 (m, ₁ H), 4.58-4.65 (m, 1H), 5.14 (t, J=7.4Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.83 (dd, J=8.8, 1.9 Hz, 1H), 8.14 (d,J=1.9 Hz, 1H); MH⁺ at m/z=292; Anal. Calc'd for C₁₁ H₈ F₃ NO₅ : C,45.22; H, 3.10; N, 4.79. Found: C, 45.37; H, 2.77; N, 4.81.

REFERENCE EXAMPLE 10 Intermediate 11578-40Dihydro-3-(5-fluoro-2-nitrophenoxy)-2(3H)-furanone

Prepared from 5-fluoro-2-nitrophenol by Method A in 65% yield usingequal portions of reagents. This material was isolated as an off-whitesolid after crystallization from CH₂ Cl₂ /ether, mp 98°-100° C.; IR(KBr) 3055, 1773, 1619, 1591, 1508, 1350, 1284, 1024, 750 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.62-2.85 (m, 2H), 4.38-4.46 (m, 1H), 4.57-4.65 (m, 1H), 5.01(t, J=7.3 Hz, 1H), 7.23-7.27 (m, 1H plus CHCl₃), 7.96 (dd, J=9.1, 5.8Hz, 1H); MH⁺ at m/z=242; Anal. Calc'd for C₁₀ H₈ FNO₅ : C, 49.80; H,3.34; N, 5.81. Found: C, 49.85; H, 3.24; N, 5.78.

REFERENCE EXAMPLE 11 Intermediate 11578-38Dihydro-3-(5-methyl-2-nitrophenoxy)-2(3H)-furanone

Prepared from 5-methyl-2-nitrophenol by Method A in 22% yield usingequal portions of reagents. This material was crystallized from CH₂ Cl₂/ether to afford a white solid, mp 68°-70° C.; IR (KBr) 3003, 2950,2928, 1774, 1516, 1355, 1189, 1023, 947 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.43(s, 3H), 2.58-2.81 (m, 2H), 4.35-4.43 (m, 1H), 4.55-4.62 (m, 1H), 4.99(t, J=7.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.79 (d, J=8.3Hz, 1H); MH+ at m/z=238; Anal. Calc'd for C₁₁ H₁₁ NO₅ : C, 55.70; H,4.67; N, 5.90. Found: C, 55.68; H, 4.62; N, 5.85.

REFERENCE EXAMPLE 12 Intermediate 11578-22-PrecursorDihydro-3-(4,6-dichloro-2-nitrophenoxy)-2(3H)-furanone

Prepared from 4,6-dichloro-2-nitrophenol by Method A in 20% yield as anorange solid and used without further purification; IR (KBr) 3086, 1779,1542, 1457, 1353, 1250, 1222, 1152, 1066, 995, 877 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.62-2.81 (m, 2H), 4.35-4.42 (m, 1H), 4.59-4.66 (m, 1H), 5.02(t, J=6.6 Hz, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.86 (d, J=2.6 Hz); MH⁺ atm/z 292.

REFERENCE EXAMPLE 13 Intermediate 9086-183-13,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Method B

Intermediate 9086-181-1, (11.9 g, 1 eq, Reference Example 1) was reactedwith H₂ at 50 psi in a Parr shaker bottle containing 10% Pd/C (1.8 g,15% w/w) in EtOH (200 ml) for 13 h. The catalyst was removed byfiltration and the filtrate concentrated under vacuum. The crude productwas triturated with hot Et₂ O to afford the benzoxazinone in 87% yieldas a white powder, mp 65°-69° C.; IR (KBr) 3298, 3076, 2993, 2917, 1677,1613, 1505, 1439, 1410, 1312, 1275, 1231, 1119, 1104, 1059, 805, 745,689 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.29 (br s, 1H), 7.01-6.95 (m, 3H), 6.82(m, 1H), 4.76 (dd, J=7.6, 5.5 Hz, 1H), 3.91 (m, 2H), 2.35-2.13 (m, 3H).Calc'd for C₁₀ H₁₁ NO₃ : C 62.17, H 5.74, N 7.25. Found: C 62.01, H5.48, N 6.95.

REFERENCE EXAMPLE 14 Intermediate 11653-189A3,4-Dihydro-2-(2-hydroxyethyl)-7-methoxy-3-oxo-2H-1,4-benzoxazine

Method C

NaBH₄ (2.7 g, 6 eq.) was gradually added to a stirring mixture ofintermediate 11653-187 (3.0 g, 11.8 mmol, Reference Example 4) andNiCl₂.6H₂ O (11.2 g, 4 eq.) in methanol (75 ml) at 0° C. The resultingdark reaction was allowed to return to room temperature slowly. After 2days, 2N HCl was carefully added to the reaction mixture until gasevolution stopped. The resulting mixture was diluted with water andextracted with EtOAc. The combined EtOAc layers were washed withsaturated NaHCO₃ then concentrated in vacuo to afford a 66% yield of apale yellow solid, mp 123°-126° C.; MS (Cl) MH⁺ 224; IR (KBr) 3475,3307, 3188, 3066, 2931, 2892, 2835, 1769, 1664, 1450, 1327, 1258, 1224,925 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 10.15 (br s, 1H), 6.80 (d, 1H, J=8.5 Hz),6.52 (d, 1H, J=2.6 Hz), 6.46 (dd, 1H, J=2.6, 8.5 Hz), 4.67 (dd, 1H,J=4.6, 8.8 Hz), 4.05 (t, 1H, J=5.4 Hz), 3.79 (m, 2H), 3.74 (s, 3H), 2.16(m, 1H), 2.01 (m, 1H). Anal. Calc'd for C₁₁ H₁₃ NO₄ : C 59.19, H 5.87, N6.27. Found: 58.87, 5.80, N 6.09.

REFERENCE EXAMPLE 15 Intermediate 11653-29A3,4-Dihydro-2-(2-hydroxyethyl)-7-nitro-3-oxo-2H-1,4-benzoxazine

Method D

2-amino-5-nitrophenol (13.5 g, 87.6 mmol, 1 eq.) andα-bromo-γ-butyrolactone (8.0 ml, 96.3 mmol, 1.1 eq.) were added to astirring mixture of DMF (80 ml) and potassium carbonate (12.1 g, 87.6mmol). After refluxing 5 hours and returning to room temperature, thereaction was poured into an equal volume of ice water and was stirred 15minutes before being filtered. The resulting brown solid was dried invacuo at 65° C. to afford a 45% yield of the product, mp 177°-178° C.;MS (FAB) MH⁺ 239; IR (KBr) 3541, 3204, 3095, 3037, 2929, 2888, 1699,1599, 1508, 1480, 1417, 1389, 1342, 1299, 1136, 1034, 798, 617, 499 cm⁻¹; ¹ H NMR (DMSO-d₆) δ 11.32 (br s, 1H), 7.91 (dd, 1H, J=2.4, 8.7 Hz),7.79 (s, 1H), 7.05 (d, 1H, J=8.7 Hz), 4.82 (dd, 1H, J=3.8, 9.0 Hz), 4.70(br s, 1H), 3.59 (m, 2H), 1.98 (m, 1H), 1.90 (m, 1H). Anal. Calc'd forC₁₀ H₁₀ N₂ O₅ : C 50.42, H 4.23, N 11.76. Found: C 50.37, H 4.20, N11.43.

REFERENCE EXAMPLE 16 Intermediate 12168-6-13,4-Dihydro-2-(2-hydroxyethyl)-6-methoxy-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 12168-2-1 (Reference Example 3) as a lightgrey solid in 76% yield by method B, mp 111°-113° C.; MS (Cl) 224 (MH⁺);IR (KBr) 3472, 3337, 3196, 3113, 3055, 2996, 2898, 2832, 1684, 1626,1611, 1520, 1501, 1466, 1403, 1312, 1292, 1264, 1229, 1192, 1162, 1082,796, 785 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.99 (br s, 1H), 6.91 (d, J=8.8 Hz,1H), 6.52 (dd, J=8.8, 2.8 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 4.70 (dd,J=7.5, 5.4 Hz, 1H), 3.90 (m, 2H), 3.77 (s, 3H), 2.21 (m, 2H). HRMSCalc'd for C₁₁ H₁₃ NO₄ (MH⁺): 224.0922. Found: 224.0974.

REFERENCE EXAMPLE 17 Intermediate 10353-189-13,4-Dihydro-2-(2-hydroxyethyl)-6-methyl-3-oxo-2H-1,4-benzoxazine

Prepared by method B from intermediate 10353-186-A (Reference Example 2)and isolated in 70% yield as a white solid, MS (Cl) 208 (MH⁺); IR (KBr)3337, 3196, 3099, 2919, 1681, 1609, 1523, 1498, 1409, 1365, 1232, 1058,806 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.96 (br s, 1H), 6.90 (d, J=9.1 Hz, 1H),6.80 (d, 9.1 Hz, 1H), 6.61 (s, 1H), 4.72 (apparent t, J=7.3 Hz, 1H),3.90 (apparent q, J=5.4 Hz, 2H), 2.32-2.15 (m, 3H), 2.30 (s, 3H). Anal.Calc'd for C₁₁ H₁₃ NO₃ : C 63.76, H 6.32, N 6.76. Found: C 63.54, H6.20, N 6.76.

REFERENCE EXAMPLE 18 Intermediate 10353-184-B3,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-trifluoromethyl-2H-1,4-benzoxazine

Prepared from intermediate 11578-50 (Reference Example 9 by method B andisolated in 54% yield as a fluffy white solid, MS (Cl) 262 (MH⁺); IR(KBr) 3468, 3202, 3113, 3044, 2962, 2888, 1696, 1622, 1496, 1402, 1336,1215, 1159, 1124, 1111, 1058, 878, 827, 807 cm⁻¹ ; ¹ H NMR (CDCl₃) δ8.01 (br s, 1H), 7.28 (m, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.05 (s, 1H),4.86 (dd, J=8.2, 5.2 Hz, 1H), 3.92 (apparent dd, J=12.7, 5.6 Hz, 2H),2.38-2.17 (m, 1H), 1.92 (t, J=5.6 Hz, 1H). Calc'd for C₁₁ H₁₀ F₃ NO₃ : C50.58, H 3.86, N 5.36. Found: C 50.52, H 3.86, N 5.28. HRMS Calc'd forC₁₁ H₁₀ F₃ NO₃ (MH⁺): 262.0691. Found: 262.0740.

REFERENCE EXAMPLE 19 Intermediate 11578-283,4-Dihydro-2-(2-hydroxyethyl)-5-methyl-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-25 (Reference Example 5) by Method Cusing 3 eq of NiCl₂.6H₂ O and 6 eq of NaBH₄, and isolated by flashchromatography (ether elution) in 39% yield as a white solid, mp147°-149° C.; IR (KBr) 3221, 1683, 1502, 1480, 1266, 1225, 1099, 1057,770, 723 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.14-2.32 (m, 3H), 2.27 (s, 3H), 4.71(q, J=5.3 Hz, 2H), 4.71 (dd, J=5.5, 7.4 Hz, 1H), 6.82-6.94 (m, 3H), 8.01(br s, 1H); MH+ at m/z=208; Anal. Calc'd for C₁₁ H₁₃ NO₃ : C, 63.76: H,6.32; N, 6.76. Found: C, 63.38; H, 6.24; N, 6.72.

REFERENCE EXAMPLE 20 Intermediate 11578-686-Chloro-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-61 (Reference Example 6) by Method Cusing 3 eq of NiCl₂.6H₂ O and 6 eq of NaBH₄. Isolated in 66% yield as awhite solid, mp 135°-138° C.; IR (KBr) 3475, 2956, 1690, 1498, 1385,1059, 809 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 1.95-2.08 (m, 1H), 2.12-2.23 (m,1H), 3.33 (br s, 1H plus DHO), 3.77-3.82 (m, 2H), 4.69 (dd, J=8.9, 4.4Hz, 1H), 6.87 (s, 2H), 6.92 (s, 1H), 10.5 (br s, 1H); MH⁺ at m/z=228;Anal. Calc'd for C₁₀ H₁₀ ClNO₃ : C, 52.76; H, 4.43; N, 6.15. Found: C,53.15; H, 4.50; N, 6.16.

REFERENCE EXAMPLE 21 Intermediate 11578-726-Carbomethoxy-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-62 (Reference Example 7) by Method Cusing 3 eq of NiCl₂.6H₂ O and 6 eq of NaBH₄. and isolated from EtOAcextraction in 51% yield as a white solid, mp 167°-169° C.; IR (KBr)3428, 1729, 1688, 1494, 1400, 1305, 1214, 1049, 764 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 1.93-2.05 (m, 1H), 2.10-2.16 (m, 1H), 3.34 (v br s, 1H),3.75-3.78 (m, 2H), 3.86 (s, 3H), 4.77 (dd, J=9.1, 4.1 Hz, 1H), 7.00 (d,J=8.2 Hz, 1H), 7.57-7.62 (m, 2H), 10.65 (s, 1H); Anal. Calc'd for C₁₂H₁₃ NO₅.0.2H₂ O: C, 56.56; H, 5.30; N, 5.50. Found: C, 56.71; H, 5.18;N, 5.35.

REFERENCE EXAMPLE 22 Intermediate 11578-363,4-Dihydro-2-(2-hydroxyethyl)-6-phenyl-3-oxo-2H-1,4-benzoxazine

Prepared by intermediate 11578-32 (Reference Example 8) by Method C in55% yield and was isolated as a white crystalline solid, mp 170°-171°C.; IR (KBr) 3428, 1682, 1605, 1489, 1403, 1237, 1030, 863, 762 cm⁻¹ ; ¹H NMR (DMSO-d₆) δ 1.81-1.90 (m, 1H), 1.92-2.01 (m, 1H), 3.53-3.63 (m,2H), 4.69 (dd, J=9.2, 3.9 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 7.13 (d,J=2.0 Hz, 1H), 7.21 (dd, J=8.4, 2.1 Hz, 1H), 7.31-7.36 (m, 1H), 7.45 (t,J=7.5 Hz, 2H), 7.54 (d, J=7.3 Hz, 2H), 10.78 (s, 1H); MH⁺ at m/z=270;Anal. Calc'd for C₁₆ H₁₅ NO₃ : C, 71.36; H, 5.61; N, 5.20. Found: C,71.06; H, 5.53; N, 5.16.

REFERENCE EXAMPLE 23 Intermediate 11578-423,4-Dihydro-7-fluoro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-40 (Reference Example 10) by Method C(reaction time of 3 days) in 43% yield to afford a white solid, mp136°-138° C.; IR (KBr) 3474, 3199, 3087, 1676, 1514, 1425, 1150, 1113,1054, 845 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 1.95-2.07 (m, 1H), 2.12-2.23 (m,1H), 3.79 (q, J=5.2 Hz, 2H), 4.01 (t, J=5.4 Hz, 1H), 4.71 (dd, J=8.8,4.5 Hz, 1H), 6.59-6.70 (m, 2H), 6.85 (dd, J=8.6, 5.5 Hz, 1H), 10.34 (brs, 1H); MH⁺ at m/z=121; Anal. Calc'd for C₁₀ H₁₀ FNO₃ : C, 56.87; H,4.77; N, 6.63. Found: C, 56.75; H, 4.74; N, 6.56.

REFERENCE EXAMPLE 24 Intermediate 11578-453,4-Dihydro-2-(2-hydroxyethyl)-7-methyl-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-38 (Reference Example 11) by Method Cto afford a white crystalline solid in 49% yield after crystallizationfrom EtOAc, mp 143°-144° C.; IR (KBr) 3468, 3069, 1664, 1520, 1421,1260, 1154, 1135, 1057, 931, 802 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 1.72-1.86(m, 1H), 1.87-2.00 (m, 1H), 2.21 (s, 3H), 3.54-3.60 (m, 2H), 4.59 (dd,J=9.4, 3.9 Hz, 1H), 4.65 (t, J=5.3 Hz, 1H), 6.72-6.78 (m, 3H), 10.58 (s,1H); MH+ at m/z=208; Anal. Calc'd for C₁₁ H₁₃ NO₃ : C, 63.76; H, 6.32;N, 6.76. Found: C, 63.73; H, 6.30; N, 6.67.

REFERENCE EXAMPLE 25 Intermediate 11578-226,8-Dichloro-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from dihydro-3-(3,5-dichloro-2-nitrophenoxy)-2-(3H)-furanone byMethod C to afford the product as a white solid in 72% yield, mp174°-176° C.; IR (KBr) 3056, 1702, 1598, 1478, 1386, 1227, 1055, 853cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 1.77-1.87 (m, 1H), 1.89-1.95 (m, 1H),3.55-3.63 (m, 2H), 4.72 (t, J=5.2 Hz, 1H), 4.82 (dd, J=9.6, 3.7 Hz, 1H),6.86 (d, J=2.3 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 11.00 (br s, 1H); MH+ atm/z=262; Anal. Calc'd for C₁₀ H₉ Cl₂ NO₃ : C, 45.83; H, 3.46; N, 5.34.Found: C, 45.82; H, 3.49; N, 5.29.

REFERENCE EXAMPLE 26 Intermediate 11653-20A3,4-Dihydro-2-(2-hydroxyethyl)-6-nitro-3-oxo-2H-1,4-benzoxazine

Prepared from 2-amino-4-nitrophenol by method D in 35% yield, mp173.5°-175° C.; MS (FAB) MH⁺ 239; IR (KBr) 3401, 3092, 2932, 1595, 1536,1499, 1323, 1213, 1144, 1100, 945, 474 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 11.06(br s, 1H), 7.85 (dd, 1H, J=2.59, 8.90 Hz), 7.74 (d, 1H, J=2.54 Hz),7.17 (d, 1H, J=8.90 Hz), 4.88 (dd, 1H, J=3.88, 8.90 Hz), 4.71 (m, 1H),3.56 (m, 2H), 2.03 (m, 1H), 1.90 (m, 1H). Anal. Calc'd for C₁₀ H₁₀ N₂ O₅: C 50.42, H 4.23, N 11.76. Found: C 50.48, H 4.21, N 11.44.

REFERENCE EXAMPLE 27 Intermediate 11653-156-A3,4-Dihydro-6-fluoro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from 2-amino-4-fluorophenol by method D in 22% yield, mp126°-129.5° C.; MS (Cl) MH⁺ 212; IR (KBr) 3349, 3199, 3109, 3054, 2981,2893, 1621, 1517, 1500, 1364, 1105, 1009, 946 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ10.78 (br s, 1H), 6.98 (dd, 1H, J=5.1, 8.8 Hz), 6.77 (d, 0.5H, J=3.0Hz), 6.74 (d, 0.5H, J=3.0 Hz), 6.70 (m, 0.5H), 6.67 (d, 0.5H, J=3.0 Hz),4.65 (m, 2H), 3.59 (m, 2H), 1.96 (m, 1H), 1.79 (m, 1H). Anal. Calc'd forC₁₀ H₁₀ FNO₃ : C 56.87, H 4.77, N 6.63 Found: C 56.55, H 4.91, N 6.54.

REFERENCE EXAMPLE 28 Intermediate 12168-5-13,4-Dihydro-2-(2-t-butyldimethylsilyloxyethyl)-6-methyl-3-oxo-2H-1,4-benzoxazine

Method E

Intermediate 10353-189-1 (1.6 g, 1 eq, Reference Example 17), wasdissolved in DMF (4 ml) and treated, sequentially, with chlorot-butyldimethylsilane (1.4 g, 1.2 eq) and imidazole (1.3 g, 2.5 eq)while stirring in a nitrogen atmosphere. After 18 h, the reactionmixture was diluted with CH₂ Cl₂ and washed with water. The organiclayer was concentrated and the product isolated in 93% yield, as a whitepowder by crystallization from MeOH/water, MS (Cl) 322 (MH⁺); IR (KBr)2953, 2927, 2883, 2856, 1698, 1609, 1523, 1496, 1360, 1234, 1119, 1093,842, 832, 811, 778 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.27 (br s, 1H), 6.86 (d,J=8.1 Hz, 1H), 6.76 (dd, J=8.1, 1.7 Hz, 1H), 6.61 (d, J=1.7 Hz, 1H),4.72, (dd, J=9.7, 3.7 Hz, 1H), 3.95-3.78 (m, 2H), 2.28 (s, 3H), 2.20 (m,1H), 2.00 (m, 1H), 0.90 (s. 9H), 0.70 (s, 3H). Anal, Calc'd for C₁₇ H₂₇NO₃ Si: C 63.51, H 8.47, N 4.36. Found: C 63.90, H 8.44, N 4.28.

REFERENCE EXAMPLE 29 Intermediate 12168-8-13,4-Dihydro-2-(2-t-butyldimethylsilyloxyethyl)-3-oxo-6-trifluoromethyl-2H-1,4-benzoxazine

Prepared from intermediate 10353-184-B (Reference Example 18) by methodE in 90% yield, as a white solid, MS (Cl) 376 (MH⁺); IR (KBr) 3027,3076, 2956, 2931, 2883, 2859, 1698, 1615, 1495, 1390, 1335, 1257, 1222,1164, 1125, 1095, 1069, 956, 833, 777 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.59 (brs, 1H), 7.25, (m, 1H), 7.06 (m, 2H), 4.85 (dd, J=9.2, 3.8 Hz, 1H), 3.85(m, 2H), 2.23 (m, 1H), 2.02 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06(s, 3H). Calc'd for C₁₇ H₂₄ F₃ NO₃ Si: C 54.38, H 6.44, N 3.73. Found: C54.34, H 6.45, N 3.73. HRMS Calc'd for C₁₇ H₂₄ F₃ NO₃ Si (MH⁺):376.1556. Found: 376.1570.

REFERENCE EXAMPLE 30 Intermediate 10353-188-A3,4-Dihydro-2-(2-t-butyldimethylsilyloxyethyl)-3-oxo-2H-pyrido2,3-b!-1,4-oxazine

Prepared from 3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-pyrido2,3-b!-1,4-oxazine by method E in 91% yield as off-white flakes MS (Cl)309 (MH⁺); IR (KBr) 3053, 2955, 2884, 2857, 1699, 1610, 1510, 1463,1375, 1357, 1278, 1256, 1092, 836, 775 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 10.40(br s, 1H), 8.04 (dd, J=5.4, 1.4 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.00(dd, J=7.7, 5.4 Hz, 1H), 4.83 (dd, J=9.5, 4.1 Hz, 1H), 3.84 (m, 2H),2.25 (m, 1H), 2.03 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).HRMS Calc'd for C₁₅ H₂₄ N₂ O₃ Si (MH⁺): 309.1634. Found: 309.1608.

REFERENCE EXAMPLE 31 Intermediate 11653-232-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-29A (Reference Example 15) by method Eand isolated by recrystallization from Et₂ O/hexane, mp 152°-157° C.; MS(FAB) MH⁺ 353; IR (KBr) 3548, 3209, 3094, 2936, 2889, 1702, 1600, 1529,1509, 1483, 1418, 1390, 1344, 1229, 1133, 1035 cm⁻¹ ; ¹ H NMR (CDCl₃) δ9.45 (br s, 1H), 7.95 (dd, 1H, J=2.4 8.6 Hz), 7.91 (d, 1H, J=2.3 Hz),6.98 (d, 1H, J=8.6 Hz), 4.93 (dd, 1H, J=3.9, 9.0 Hz), 3.90 (m, 2H), 2.28(m, 1H), 2.04 (m, 1H), 0.93 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). Anal.Calc'd for C₁₆ H₂₄ N₂ O₅ Si: C 54.52, H 6.86, N 7.95. Found: C 54.14, H6.64, N 8.18.

REFERENCE EXAMPLE 32 Intermediate 11653-33A2-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-20A (Reference Example 26) by method Ein 92% yield, mp 121.5°-124.5° C.; MS (FAB) MH⁺ 353; IR (KBr) 3190,3125, 3055, 2952, 2884, 2426, 1921, 1623, 1446, 1296, 1281, 1209, 1004,925, 682, 512 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.10 (dd, 1H, J=2.65, 8.79 Hz),7.75 (d, 1H, J=2.56 Hz), 6.96 (dd, 1H, J=4.99, 8.68 Hz), 4.80 (dd, 1H,J=3.88, 9.30 Hz), 3.78 (m, 2H), 2.18 (m, 1H), 1.95 (m, 1H), 0.82 (s,9H). 0.01 (d, 6H, J=3.51 Hz). Anal. Calc'd for C₁₆ H₂₄ N₂ O₅ : C 54.52,H 6.86, N 7.95. Found: C 54.18, H 6.51, N 8.29.

REFERENCE EXAMPLE 33 Intermediate 11653-163-A12-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-6-fluoro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-156-A (Reference Example 27) by methodE in 77% yield mp 84°-86° C.; MS (Cl) MH⁺ 326; IR (KBr) 3101, 3066,2951, 2931, 2893, 2857, 1692, 1622, 1518, 1499, 1469, 1386, 1292, 1248,1108, 1006, 812 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.86 (br s, 1H), 6.92 (dd, 1H,J=4.9, 8.8 Hz), 6.67 (m, 1H), 6.60 (dd, 1H, J=2.9, 8.5 Hz), 4.73 (dd,1H, J=3.7, 9.5 Hz), 3.91-3.78 (m, 2H), 2.26 (m, 1H), 1.98 (m, 1H), 0.89(s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). Anal. Calc'd for C₁₆ H₂₄ FNO₃ Si: C59.05, H 7.43, N 4.30. Found: C 59.01, H 7.54, N 4.16.

REFERENCE EXAMPLE 34 Intermediate 11578-312-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-5-methyl-3-oxo-2H-1,4-benzoxazine

Prepared from 11578-28 (Reference Example 19) by Method E and isolateddirectly from the reaction mixture in 24% yield as a white solid, byadding water and collecting the precipitate, mp 90°-92° C.; IR (KBr)2953, 2927, 2855, 1693, 1502, 1482, 1390, 1360, 1250, 1119, 1093, 959,837, 780, 769 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90(s, 9H), 1.92-2.03 (m, 1H), 2.17-2.26 (m, 1H), 2.26 (s, 3H), 3.78-3.93(m, 2H), 4.72 (dd, J=3.7, 9.7 Hz, 1H), 6.81-6.92 (m, 3H), 8.04 (br s,1H); Anal. Calc'd for C₁₇ H₂₇ NO₃ Si: C, 63.51; H, 8.47; N, 4.36. Found:C, 63.50; H, 8.53; N, 4.24.

REFERENCE EXAMPLE 35 Intermediate 11578-702-(2-tert-Butyldimethylsiloxyethyl)-6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine

Prepared from 11578-68 (Reference Example 20) by Method E using 1 eq ofimidazole and t-butyldimethylsilylchloride and isolated in 44% yield asa white solid after trituration with hexane, mp 86°-89° C.; MH⁺ atm/z=342; IR (KBr) 2955, 2928, 2881, 2857, 1700, 1496, 1400, 1360, 1231,1124, 1094, 954, 834 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.07 (s, 3H), 0.08 (s,3H), 0.89 (s, 9H), 1.96-2.05 (m, 1H), 2.16-2.24 (m, 1H), 3.81-3.89 (m,2H), 4.76 (dd, J=9.4, 3.7 Hz, 1H), 6.83 (d, J=2 Hz, 1H), 6.89-6.98 (m,2H), 8.80 (br s, 1H). Anal. Calc'd for C₁₆ H₂₄ ClNO₃ Si: C, 56.21; H,7.08; N, 4.10. Found: C, 56.59; H, 7.17; N, 4.04.

REFERENCE EXAMPLE 36 Intermediate 11578-442-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazine

Prepared from 11578-42 (Reference Example 23) by Method E and isolateddirectly from the reaction mixture in 80% yield as a white solid, byadding water and collecting the precipitate, mp 100°-102° C.; IR (KBr)2958, 2928, 2888, 2854, 1697, 1667, 1517, 1428, 1367, 1252, 1150, 1112,1084, 833, 779 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90(s, 9H), 1.96-2.05 (m, 1H), 2.16-2.27 (m, 1H), 3.80-3.91 (m, 2H), 4.77(dd, J=9.5, 3.8), 6.64-6.80 (m, 3H), 9.05 (br s, 1H); Anal. Calc'd forC₁₆ H₂₄ FNO₃ Si: C, 59.05; H, 7.43; N, 4.30. Found: C, 58.98; H, 7.39;N, 4.27.

REFERENCE EXAMPLE 37 Intermediate 11578-302-(2-tert-Butyldimethylsiloxyethyl)-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine

Prepared from 11578-22 (Reference Example 25) by Method E and isolateddirectly from the reaction mixture in 90% yield as a white solid, byadding water and collecting the precipitate, mp 118°-120° C.; IR (KBr)2954, 2931, 2885, 2857, 1702, 1480, 1404, 1254, 1085, 838, 778 cm⁻¹ ; ¹H NMR (CDCl₃) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.94-2.03 (m,1H), 2.15-2.21 (m, 1H), 3.77-3.89 (m, 1H), 3.93 (td, J=9.7, 4.4 Hz, 1H),4.89 (dd, J=9.8, 3.5 Hz, 1H), 6.78 (d, J=2.3 Hz, 1H), 7.05 (d, J=2.3 Hz,1H), 9.39 (br s, 1H); Anal. Calc'd for C₁₆ H₂₃ Cl₂ NO₃ Si: C, 51.06; H,6.16; N, 3.72. Found: C, 50.72; H, 5.87; N, 3.82.

REFERENCE EXAMPLE 38 Intermediate 11578-77-Precursor2-(2-tert-Butyldimethylsiloxyethyl)-6-carbomethoxy3,4-dihydro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-72 (Reference Example 21) by Method Ein 80% yield. The crude product was used without purification, MH⁺ atm/z=366.

REFERENCE EXAMPLE 39 Intermediate 12168-10-14-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-6-methyl-2H-1,4-benzoxazine

Prepared in two steps beginning from intermediate 12168-5-1 (ReferenceExample 28).

Method F

A solution of the silylated alcohol (2.17 g, 1 eq) in DMF (20 ml), wastreated with NaH (60% oil dispersion, 0.27 mg, 1 eq) in one portion andstirred at room temperature in an nitrogen atmosphere for 20 min,followed by addition of 3-chlorobenzyl bromide (0.89 ml, 1 eq). After 14h, the crude reaction mixture was poured into cold water and extractedwith EtOAc. The combined organic extract was washed with brine andconcentrated under vacuum. The crude product was carried on to the nextstep without further purification.

Method G

The product from Method F was dissolved in THF (15 ml) andtetrabutylammonium fluoride (1M solution in THF, 13 ml, 2 eq) was added.After stirring at room temperature for 8 h, the reaction mixture wasconcentrated under vacuum. The crude product was subjected to flashchromatography, eluting with EtOAc, and additionally purified bytrituration with hot hexanes to afford the product in 93% overall yield,as a white solid, mp 75°-78° C.; MS (Cl) 332 (MH⁺); IR (KBr) 3501, 3451,3062, 1969, 2937, 2874, 1660, 1610, 1598, 1575, 1513, 1473, 1432, 1387,1321, 1280, 1258, 1106, 1067, 1061, 934, 775, 698 cm⁻¹ ; ¹ H NMR (CDCl₃)δ 7.27 (m, 3H), 7.17 (m, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.79 (d, J=7.0 Hz,1H), 6.63 (s, 1H), 5.17 (d, J=16.3 Hz, 1H), 5.08 (d, J=16.3 Hz, 1H),4.80 (dd, J=7.6, 5.5 Hz, 1H), 3.92 (apparent q, J=5.8 Hz, 2H), 2.29-2.17(m, 3H), 2.23 (s, 3H). HRMS Calc'd for C₁₈ H₁₈ ClNO₃ (MH⁺): 332.1053.Found: 332.1041.

REFERENCE EXAMPLE 40 Intermediate 10353-191-14-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-6-methyl-2H-pyrido2,3-b!-1,4-oxazine

Prepared from intermediate 10353-188-A (Reference Example 30) by methodsF and G, alkylating with 3-chlorobenzyl bromide, in 69% overall yield asan off-white powder mp 80°-81° C.; MS (Cl) 319 (MH⁺); IR (KBr) 3525,3446, 2928, 2874, 1667, 1600, 1574, 1465, 1411, 1362, 1325, 1285, 1230,1205, 1121, 1096, 1064, 797, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.04 (dd,J=4.8, 1.5 Hz, 1H), 7.42 (s, 1H), 7.37-7.18 (m, 4H), 6.96 (dd, J=7.9,4.8 Hz, 1H), 5.31 (s, 2H), 4.85 (dd, J=7.5, 5.4 Hz, 1H), 3.90 (m, 2H),2.35-2.16 (m, 2H), 2.04 (t, 5.6 Hz, 1H). HRMS Calc'd for C₁₆ H₁₅ ClN₂ O₃(MH⁺): 319.0849. Found: 319.0857.

REFERENCE EXAMPLE 41 Intermediate 10353-28-14-(4-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 4-chlorobenzyl chloride, in 63%overall yield as a white solid mp 86°-88° C.; MS (Cl) 300 (MH⁺ -H₂ O);IR (KBr) 3496, 2977, 2890, 1656, 1607, 1501, 1466, 1401, 1297, 1250,1088, 1061, 1018, 795, 747 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.28 (d, J=8.5 Hz,2H), 7.18 (d, J=8.5 Hz, 2H), 7.05-6.87 (m, 3H), 6.83 (d, J=8.0 Hz, 1H),5.12 (s, 2H), 4.83 (dd, J=7.5, 5.5 Hz, 1H), 3.92 (apparent t, J 5.7 Hz,2H), 2.38-2.15 (m, 3H). Calc'd for C₁₇ H₁₆ ClNO₃ : C 64.26, H 5.08, N4.41. Found: C 64.01, H 5.08, N 4.37.

REFERENCE EXAMPLE 42 Intermediate 9086-189-14-(2-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 2-chlorobenzyl chloride, in 65%overall yield as white powder mp 90°-91.5° C.; MS (Cl) 318 (MH⁺ -H₂ O);IR (KBr) 3482, 2935, 2881, 1663, 1607, 1594, 1505, 1466, 1443, 1407,1320, 1306, 1283, 1252, 1063, 749 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.42 (dd,J=7.6, 1.5 Hz, 1H), 7.30-7.13 (m, 2H), 7.08-9.88 (m, 4H), 6.73 (dd,J=7.9, 1.3 Hz, 1H), 5.25 (d, J=17.2 Hz, 1H), 5.23 (d, J=17.3 Hz, 1H),4.88 (dd, J=7.5, 5.5 Hz, 1H), 3.95 (apparent q, J=5.9 Hz, 2H), 2.40-2.20(m, 2H), 2.19 (t, J=5.9 Hz, 1H). Anal. Calc'd for C₁₇ H₁₆ ClNO₃ : C64.26, H 5.08, N 4.41. Found: C 64.41, H 5.00, N 4.47.

REFERENCE EXAMPLE 43 Intermediate 12168-25-14-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-6-methoxy2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-6-methoxy-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 3-chlorobenzyl bromide, in 80%overall yield. Isolated by crystallization from EtOH/water to afford awhite powder, MS (Cl) 348 (MH⁺); IR (KBr) 3501, 3053, 3021, 2959, 2933,2876, 2838, 1664, 1618, 1600, 1575, 1512, 1466, 1445, 1435, 1390, 1361,1337, 1313, 1272, 1237, 1201, 1173, 1107, 1078, 1049, 1030 cm⁻¹ ; ¹ HNMR (CDCl₃) δ 7.27-7.20 (m, 3H), 7.13 (m, 1H), 6.94 (d, J=8.8 Hz, 1H),6.52 (dd, J=9.1, 2.7 Hz, 1H), 6.41 (d, J=2.7 Hz, 1H), 5.12 (d, J=16.2Hz, 1H), 4.79 (dd, J=8.2, 5.4 Hz, 1H), 3.92 (m, 2H), 3.68 (s, 3H),3.39-2.16 (m, 2H), 2.17 (t, J=5.9 Hz, 1H). Anal. Calc'd for C₁₈ H₁₈ClNO₄.0.25 H₂ O: C 61.37, H 5.29, N 3.98. Found: C 61.35, H 5.14, N3.95.

REFERENCE EXAMPLE 44 Intermediate 11578-414-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-6-phenyl-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-6-phenyl-2H-1,4-benzoxazineby Methods F and G, alkylating with 3-chlorobenzyl bromide, to afford awhite crystalline solid in 27% overall yield, mp 119°-121° C.; IR (KBr)3517, 1659, 1487, 1435, 1387, 1282, 1260, 1060, 760 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.22-2.38 (m, 3H), 3.95 (v br s, 2H), 4.90 (dd, J=7.6, 5.5 Hz,1H), 5.18 (ABq, J_(AB) =17.1 Hz, 2H), 7.04 (d, J=1.9 Hz, 1H), 7.08 (d,J=8.3 Hz, 1H), 7.15-7.42 (m, 10H); MH⁺ at m/z=394; Anal. Calc'd for C₂₃H₂₀ ClNO₃ : C, 70.14; H, 5.12; N, 3.56. Found: C, 70.10; H, 5.11; N,3.51.

REFERENCE EXAMPLE 45 Intermediate 10508-24-A4-(3-Fluorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 3-flourobenzyl chloride, in 49%overall yield and isolated as a gummy solid; IR (KBr) 3425, 1683, 1501,1401, 1252, 1061, 751 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.16-2.38 (m, 3H), 3.92(t, J=5.8 Hz, 2H), 4.85 (dd, J=7.6, 5.5 Hz, 1H), 5.14 (s, 2H), 6.82-6.85(m, 1H), 6.90-7.08 (m, 6H), 7.26-7.33 (m, 1H); MH+ at m/z=302; Anal.Calc'd for C₁₇ H₁₆ FNO₃ : C, 67.76; H, 5.35; N, 4.65. Found: C, 67.48;H, 5.34; N, 4.57.

REFERENCE EXAMPLE 46 Intermediate 10840-333,4-Dihydro-2-(2-hydroxyethyl)-4-(4-methylbenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G alkylating with 4-methylbenzyl chloride, in 50%overall yield. This material was crystallized from ether to afford awhite solid, mp 92°-94° C.; IR (KBr) 3496, 1659, 1503, 1405, 1304, 1283,1248, 1063, 801 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.18-2.36 (m, 5H), 3.91 (q,J=5.7, 2H), 4.83 (dd, J=7.4, 5.7, 1H), .5.12 (s, 2H), 6.90-7.00 (m, 4H),7.13 (s, 4H); MH⁺ at m/z=298; Anal. Calc'd for C₁₈ H₁₉ NO₃ : C, 72.71;H, 6.44; N, 4.71. Found: C, 72.71; H, 6.48; N, 4.65.

REFERENCE EXAMPLE 47 Intermediate 10508-193,4-Dihydro-2-(2-hydroxyethyl)-4-(4-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 4-methoxybenzyl chloride, in 48%overall yield after flash chromatography eluting with EtOAc/hexane, mp80°-82° C.; IR (KBr) 3496, 1660, 1515, 1501, 1412, 1250, 1057, 754 cm⁻¹; ¹ H NMR (CDCl₃) δ 2.00 (v br s, 1H), 2.16-2.37 (m, 2H), 3.77 (s, 3H),3.91 (t, J=6.1 Hz, 2H), 4.82 (dd, J=7.5, 5.6 Hz, 1H), 5.09 (s, 2H), 6.85(d, J=8.7 Hz, 2H), 6.91-7.00 (m, 4H), 7.18 (d, J=8.7 Hz, 2H); MH+ atm/z=314; Anal. Calc'd for C₁₈ H₁₉ NO₄ : C, 68.99; H, 6.11; N, 4.47.Found: C, 69.22; H, 6.10; N, 4.35.

REFERENCE EXAMPLE 48 Intermediate 10005-181-14-(3,5-Dichlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 3,5-dichlorobenzyl chloride, in 89%overall yield. A sample was crystallized from CH₂ Cl₂ /hexane/ether toafford a white solid, mp 104°-106° C.; IR (KBr) 3525, 1680, 1570, 1505,1398, 1063, 760 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.92 (br s, 1H), 2.17-2.37 (m,2H), 3.93 (t, J=5.7 Hz, 2H), 4.87 (q, J=5.4 Hz, 1H), 5.13 (ABq, J_(AB)=16.3 Hz, 2H), 6.78 (d, J=7.3 Hz, 1H), 6.93-7.05 (m, 2H), 7.12 (br d,J=1.7 Hz, 2H), 7.26-7.28 (m, 2H); Anal. Calc'd for C₁₇ H₁₅ Cl₂ NO₃ : C,57.97; H, 4.29; N, 3.98. Found: C, 57.96; H, 4.17; N, 3.87.

REFERENCE EXAMPLE 49 Intermediate 11578-716-Chloro-4-(3-chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-70 (Reference Example 35) by Methods Fand G, alkylating with 3-chlorobenzyl bromide, and isolated in 43%overall yield as a white solid, mp 90°-92° C.; IR (KBr) 3499, 1663,1601, 1497, 1433, 1386, 1324, 1267, 1091, 1050, 933, 783 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.05 (br s, 1H), 2.18-2.30 (m, 2H), 3.89-3.97 (m, 2H), 4.86(dd, J=7.7, 5.5 Hz, 1H), 5.1 (s, 2H), 6.81 (s, 1H), 6.96 (d, J=1.4 Hz,2H), 7.12-7.30 (m, 4H); MH⁺ at m/z=352; Anal. Calc'd for C₁₇ H₁₅ Cl₂ NO₃: C, 57.95; H, 4.29; N, 3.98. Found: C, 58.26; H, 4.32; N, 3.89.

REFERENCE EXAMPLE 50 Intermediate 11578-564-(3-Chlorobenzyl)-6-trifluoromethyl-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine0.2 Hydrate

Prepared from intermediate 12168-8-1 (Reference Example 29) by methods Fand G, alkylating with 3-chlorobenzyl bromide, in 96% yield as a whitecrystalline solid, mp 92°-94° C.; IR (KBr) 3520, 1671, 1454, 1330, 1299,1269, 1120, 868, 712 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.20-2.40 (m, 2H), 3.92(t, J=6.3 Hz, 2H), 4.93 (t, J=7.6 Hz, 1H), 5.14 (s, 2H), 7.07-7.16 (m,3H), 7.23-7.30 (m, 4H); MH⁺ at m/z=386; Anal. Calc'd for C₁₈ H₁₅ ClF₃NO₃.0.2H₂ O: C, 55.52; H, 3.99; N, 3.60. Found: C, 55.49; H, 3.77; N,3.53.

REFERENCE EXAMPLE 51 Intermediate 11578-776-Carbomethoxy-4-(3-chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-6-carbomethoxy-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 3-chlorobenzyl bromide, in 70%overall yield as a white solid, after trituration with hexane, IR (KBr)3468, 2952, 1688, 1452, 1285, 1260, 765 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.61(br s, 1H plus HDO), 2.17-2.39 (m, 2H), 3.86 (s, 3H), 3.93 (t, J=5.7 Hz,2H), 4.94 (dd, J=7.6, 5.5 Hz, 1H), 5.16 (s, 2H), 7.04 (d, J=8.4, 1H),7.15-7.33 (m, 4H), 7.59 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.4, 1.8 Hz, 1H);MH⁺ at m/z=376; Anal. Calc'd for C₁₉ H₁₈ ClNO₅.0.1 H₂ O: C, 60.44; H,4.86; N, 3.71. Found: C, 60.26; H, 4.60; N, 3.58.

REFERENCE EXAMPLE 52 Intermediate 11578-474-(3-Chlorobenzyl)-3,4-dihydro-7-fluoro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-44 (Reference Example 36) by Methods Fand G, alkylating with 3-chlorobenzyl bromide, in 76% overall yield.This material was isolated as an off-white solid, mp 79°-82° C.; IR(KBr) 3487, 1662, 1508, 1412, 1320, 1155, 1115, 1053, 854, 799 cm⁻¹ ; ¹H NMR (CDCl₃) δ 2.10 (t, J=4.3 Hz, 1H), 2.18-2.40 (m, 2H), 3.92 (q,J=6.0 Hz, 2H), 4.88 (t, J=5.5 Hz, 1H), 5.10 (ABq, J_(AB) =15.4 Hz, 2H),6.64 (td, J=7.9, 2.7 Hz, 1H), 6.72-6.79 (m, 2H), 7.11 (br s, 1H),7.22-7.28 (m, 3H plus CHCl₃); MH⁺ at m/z=336; Anal. Calc'd for C₁₇ H₁₅ClFNO₃ : C, 60.81; H, 4.50; N, 4.17. Found: C, 60.74; H, 4.69; N, 4.28.

REFERENCE EXAMPLE 53 Intermediate 11578-1137-Fluoro-3,4-dihydro-4-(3-fluorobenzyl)-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-44 (Reference Example 36) by Methods Fand G, alkylating with 3-fluorobenzyl chloride, to afford a white solidin 67% yield, mp 78°-79° C.; IR (KBr) 3497, 1661, 1509, 1415, 1252,1159, 1119, 1057, 937, 857,801 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.11 (t, J=5.1Hz, 1H), 2.17-2.39 (m, 2H), 3.92 (q, J=5.5 Hz, 2H), 4.87 (dd, J=7.6, 5.5Hz, 1H), 5.13 (s, 2H), 6.64 (td, J=8.0, 2.7 Hz, 1H), 6.73-6.79 (m, 2H),6.94 (t, J=8.5 Hz, 2H), 7.01 (s, J=7.7 Hz, 1H), 7.27-7.35 (m, 1H); MH⁺at m/z=320; Anal. Calc'd for C₁₇ H₁₅ F₂ NO₃ : C, 63.95; H, 4.74; N,4.39. Found: C, 63.91; H, 4.70; N, 4.30.

REFERENCE EXAMPLE 54 Intermediate 11578-1147-Fluoro-3,4-dihydro-2-(2-hydroxyethyl)-4-(2-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-44 (Reference Example 36) by Methods Fand G, alkylating with 2-nitrobenzyl chloride, to afford a white solidafter column chromatography, eluting with ether, in 76% yield. A portionof this material was crystallized from hexane, mp 123°-124° C.; IR (KBr)3510, 1655, 1527, 1509, 1357, 1157, 1127, 1063, 801 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.01 (t, J=5.1 Hz, 1H), 2.22-2.38 (m, 2H), 3.93 (q, J=5.6 Hz,2H), 4.92 (dd, J=7.54, 5.63 Hz, 1H), 5.23 (ABq, J_(AB) =16.5 Hz, 2H),6.63-6.75 (m, 2H), 6.80 (dd, J=8.7, 2.6 Hz, 1H), 7.51-7.60 (m, 2H), 8.12(s, 1H), 8.15 (d, J=7.1 Hz, 1H); MH⁺ at m/z=347; Anal. Calc'd for C₁₇H₁₅ FN₂ O₅ : C, 58.96; H, 4.37; N, 8.09. Found: C, 58.81; H, 4.37; N,8.01.

REFERENCE EXAMPLE 55 Intermediate 11578-524-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-7-methyl-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methyl-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 3-chlorobenzyl bromide, in 76% yieldas a white solid after crystallization from ether/hexane, mp 72°-74° C.;IR (KBr) 3418, 1679, 1512, 1402, 1292, 1061, 763 cm⁻¹ ; ¹ H NMR (CDCl₃)δ 2.20-2.36 (m, 3H), 2.27 (s, 3H), 3.92 (q, J=5.6 Hz, 2H), 4.83 (dd,J=7.6, 5.5 Hz, 1H), 5.10 (ABq, J_(AB) =17.0 Hz, 2H), 6.68-6.75 (m, 2H),6.84 (s, 1H), 7.10-7.14 (m, 1H), 7.22-7.29 (m, 3H); MH⁺ at m/z=332;Anal. Calc'd for C₁₈ H₁₈ ClNO₃.0.2H₂ O: C, 64.46; H, 5.53; N, 4.18.Found: C, 64.48; H, 5.51; N, 4.06.

REFERENCE EXAMPLE 56 Intermediate 11578-334-(3-Chlorobenzyl)-6,8-dichloro-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11578-30 (Reference Example 37) by Methods Fand G, alkylating with 3-chlorobenzyl bromide, in 80% yield. Thismaterial was isolated as a white foam after flash chromatography usingether/CH₂ Cl₂ (1/4); IR (KBr) 3430, 1694, 1592, 1480, 1434, 1380, 1285,1059, 933, 843, 755 cm⁻¹ ; ¹ H NMR (CDCl₃) 2.00 (t, J=5.4 Hz, 1H),2.15-2.40 (m, 2H), 3.92-4.03 (m, 2H), 4.97 (dd, J=8.8, 4.7 Hz, 1H), 5.09(s, 2H), 6.72 (d, J=2.3 Hz, 1H), 7.08 (d, J=2.2 Hz, 2H), 7.20 (s, 1H),7.26-7.30 (m, 2H plus CHCl₃); Anal. Calc'd for C₁₇ H₁₄ Cl₃ NO₃ : C,52.81; H, 3.65; N, 3.62. Found: C, 52.90; H, 3.73; N, 3.46.

REFERENCE EXAMPLE 57 Intermediate 10840-183,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-4-(2-picolyl)-2H-1,4-benzoxazine

2-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazinewas alkylated with 2-chloromethylpyridine by method F and the crudeproduct was deprotected by method H without purification.

Method H

The t-butyldimethylsiloxy intermediate was dissolved in methanol and anexcess of 6N HCl. The solution was stirred at room temperature 1 h andthen concentrated under vacuum. The aqueous residue was extracted withdichloromethane and the combined extract was washed with brine and driedover Na₂ SO₄. Removal of solvent produced the crude product which waspurified by flash chromatography in 42% yield and was isolated as awhite solid after crystallization from ether/hexane, mp 108°-111° C.; IR(KBr) 2881, 1675, 1505, 1401, 1279, 1115, 1070, 749 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.18-2.38 (m, 2H), 2.44 (br s, 1H), 3.92 (br d, J=3.8 Hz, 2H),4.86 (dd, J=7.2, 5.8 Hz, 1H), 5.27 (ABq, J_(AB) =16.3 Hz, 2H), 6.89-7.03(m, 4H), 7.17-7.24 (m, 2H), 7.64 (td, J=7.7, 1.7 Hz, 1H), 8.56 (br d,J=4.3 Hz, 1H); MH⁺ at m/z=285; Anal. Calc'd for C₁₆ H₁₆ N₂ O₃ : C,67.59; H, 5.67; N, 9.85. Found: C, 67.55; H, 5.83; N, 9.83.

REFERENCE EXAMPLE 58 Intermediate 10840-223,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-4-(4-picolyl)-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and H, alkylating with 4-chloromethylpyridine, in 12% yieldand isolated as a beige solid, mp 153°-154° C.; IR (KBr) 3204, 1679,1505, 1407, 1283, 1256, 1077, 1065, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.18-2.38 (m, 3H), 3.93 (br q, J=3.9 Hz, 2H), 4.88 (dd, J=7.7, 5.4 Hz,1H), 5.15 (s, 2H), 6.73 (d, J=7.6 Hz, 1H), 6.92 (td, J=6.7, 3.2 Hz, 1H),6.98-7.06 (m, 2H), 7.15 (d, J=5.9 Hz, 2H), 8.56 (dd, J=4.5, 1.5 Hz, 2H);MH⁺ at m/z=285; Anal. Calc'd for C₁₆ H₁₆ N₂ O₃ : C, 67.59; H, 5.67; N,9.85. Found: C, 67.67; H, 5.78; N, 9.79.

REFERENCE EXAMPLE 59 Intermediate 11578-993,4-Dihydro-2-(2-hydroxyethyl)-4-(4-phenylbenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 4-phenylbenzyl chloride, in 98%yield as a yellow crystalline solid, mp 110°-113° C.; IR (KBr) 3350,1683, 1500, 1400, 1304, 1275, 1247, 1051, 908, 758 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.21-2.38 (m, 2H), 3.94 (q, J=5.48 Hz, 2H), 4.87 (dd, J=7.5,5.61 Hz, 1H), 5.20 (ABq, J_(AB) =17.1 Hz, 2H), 6.93-7.04 (m, 4H),7.30-7.40 (m, 3H), 7.43 (t, J=7.0 Hz, 2H), 7.55 (d, J=8.1 Hz, 4H); MH⁺at m/z=360; Anal. Calc'd for C₂₃ H₂₁ NO₃ : C, 76.86; H, 5.89; N, 3.90.Found: C, 76.61; H, 5.88; N, 3.74.

4-Phenylbenzyl chloride was prepared by treating a CH₂ Cl₂ solution ofthe corresponding alcohol (1 eq) with methanesulfonyl chloride (1.1 eq)and TEA (1.1 eq) at 0° C. This solution was stirred for 16 h, treatedwith 3N HCl and the organic layer was isolated. After drying, thesolvent was evaporated to afford the 4-phenylbenzyl chloride in 64%yield, MH⁺ at m/z=202.

REFERENCE EXAMPLE 60 Intermediate 10840-1853,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-4-pentyl-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 1-chloropentane in 32% yield andisolated as a colorless oil; IR (KBr) 3424, 2956, 2932, 1680, 1500,1272, 1062, 749 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.91 (t, J=6.8 Hz, 3H),1.31-1.38 (m, 4H), 1.66 (br t, J=5.5 Hz, 2H), 2.08-2.29 (m, 2H), 2.59(br s, 1H), 3.87-3.94 (m, 2H), 4.69 (dd, J=7.3, 5.8 Hz, 1H), 6.92-7.08(m, 4H); Anal. Calc'd for C₁₅ H₂₁ NO₃ : C, 68.42; H, 8.04; N, 5.32.Found: C, 68.10; H, 7.88; N, 5.32.

REFERENCE EXAMPLE 61 Intermediate 11653-1803,4-Dihydro-2-(2-hydroxyethyl)-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

The intermediate silyl protected alcohol was prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Method F, alkylating with 3-nitrobenzyl chloride. Deprotection to theindicated product was carried out by method I.

Method I

The TBDMS-protected benzoxazine (3.1 mmol) was stirred into a milkymixture with AcOH (12 mL), THF (2 mL) and H₂ O (5 mL). This mixture wasstirred for 18 h to give a clear solution. The addition of water gave awhite solid precipitate which was filtered and dried in vacuo at 80° C.:mp 103°-104° C.; MS (Cl) MH⁺ 329; IR (KBr) 3490, 3087, 2947, 2879, 1685,1663, 1607, 1593, 1466, 1280, 1168, 976 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.15(s, 1H), 8.13 (s, 1H), 7.54 (m, 2H), 7.04 (m, 2H), 6.95 (m, 1H), 6.79(d, 1H, J=7.6 Hz), 5.28 (d, 1H, J=16.5 Hz), 5.21 (d, 1H, J=16.5 Hz),4.90 (dd, 1H, J=5.5, 7.6 Hz), 3.93 (m, 2H), 2.29 (m, 2H), 2.13 (t, 1H,J=5.6 Hz). Anal. Calc'd for C₁₇ H₁₆ N₂ O₅ : C 62.19, H 4.91, N 8.53.Found: C 61.99, H 4.91, N 8.43.

REFERENCE EXAMPLE 62 Intermediate 12279-113,4-Dihydro-2-(2-hydroxyethyl)-7-nitro-4-(4-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-23 (Reference Example 31) by methods Fand I and isolated as a yellow-orange solid in 42% yield, mp 100°-104°C.; MS (Cl) MH⁺ 374; IR (KBr) 3395, 3113, 3089, 2939, 1683, 1598, 1432,1395, 1142, 991, 914, 800, 544, 455 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 8.23 (d,2H, J=8.70 Hz), 7.92 (d, 1H, J=2.42 Hz), 7.85 (dd, 1H, J=8.85, 2.54 Hz),7.41 (d, 2H, J=8.60 Hz), 6.85 (d, 1H, J=8.93), 5.30 (d, 2H, J=4.56 Hz),5.01 (dd, 1H, J=7.76, 5.11 Hz), 3.96 (t, 2H, J=6.45 Hz), 2.30 (m, 2H),1.79 (br.s, 1H). Anal. Calc'd for C₁₇ H₁₅ N₃ O₇.0.7 H₂ O: C 52.91, H4.28, N 10.89. Found: C 53.17, H 4.36, N 10.53.

REFERENCE EXAMPLE 63 Intermediate 12279-18-A3,4-Dihydro-2-(2-hydroxyethyl)-7-methoxy-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methoxy-3-oxo-2H-1,4-benzoxazineby methods F and I, alkylating with 3-nitrobenzyl chloride, in 30%yield, mp 116°-118° C.; MS (Cl) MH⁺ 359; IR (KBr) 3306, 3086, 2926,2872, 1628, 1595, 1476, 1309, 1290, 1255, 1087, 999, 713, 458 cm⁻¹ ; ¹ HNMR (DMSO-d₆) δ 8.14 (s, 1H), 8.11 (s, 1H), 7.63 (m, 2H), 6.97 (d, 1H,J=8.93 Hz), 6.66 (d, 1H, J=2.42 Hz), 6.53 (d, 1H, J=8.87 Hz), 5.26 (s,2H), 4.87 (dd, 1H, J=8.98, 3.78 Hz), 4.72 (t, 1H, J=5.23 Hz), 3.68 (s,3H), 3.61 (m, 2H), 2.01 (m, 1H), 1.90 (m, 1H). Anal. Calc'd for C₁₈ H₁₈N₂ O₆ : C 60.33 H 5.06, N 7.82. Found: C 59.96, H 5.08, N 7.62.

REFERENCE EXAMPLE 64 Intermediate 12279-213,4-Dihydro-6-fluoro-2-(2-hydroxyethyl)-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-163-A1 (Reference Example 33) bymethods F and I, alkylating with 3-nitrobenzyl chloride, in 35% yield,mp 110°-112° C.; MS (Cl) MH⁺ 347; IR (KBr) 3483, 3077, 2945, 2872, 1620,1603, 1453, 1297, 1210, 1098, 979, 791, 742, 685, 470 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 8.16 (d, 1H, J=6.87 Hz), 8.10 (s, 1H), 7.54 (m, 2H), 6.90 (dd,1H, J=3.73, 5.12 Hz), 6.71 (m, 1H), 6.51 (dd, 1H, J=9.35, 2.76 Hz), 5.20(d, 2H, J=5.46 Hz), 4.87 (dd, 1H, J=7.60, 5.41 Hz), 3.93 (t, 2H, J=5.78Hz), 2.29 (m, 2H), 2.00 (m, 1H). Anal. Calc'd for C₁₇ H₁₅ FN₂ O₅ : C58.96, H 4.37, N 8.09. Found: C 58.57, H 4.43, N 7.89.

REFERENCE EXAMPLE 65 Intermediate 12279-13-A4-(3-Aminobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared by dissolving the intermediate t-butyldimethylsiloxy compoundfrom example 11653-180 (1.58 g, Reference Example 61) in ethanol (25ml). Fe powder (1.3 g) was added with stirring, followed by conc. HCl(12 ml). The reaction was stirred at room temperature for 16 hrs. Thereaction was filtered directly into ice water, and extracted with EtOAc.The extract was washed with brine, and concentrated under vacuum. Theresulting brown oil was rinsed in ether. After decanting the ether, theoil was scratched to produce the product as a light brown solid in 50%yield, mp 79° C.-darkens, 85°-90° C.-melts; MS (Cl) MH⁺ 299; IR (KBr)3470, 3373, 3215, 3031, 2930, 2877, 1657, 1605, 1590, 1465, 1441, 1356,1251, 1183, 1165, 1101, 1016, 995, 898, 688, 560 cm⁻¹ ; ¹ H NMR (CDCl₃)δ 7.10 (t, 1H, J=7.70 Hz), 7.10-6.20(v br.s, 2H), 6.98 (m, 2H), 6.93 (m,2H), 6.63 (d, 1H, J=7.8 Hz), 6.56 (d, s, 2H, J=8.6 Hz), 5.10 (d, 1H,J=16.0 Hz), 5.00 (d, 1H, J=16.0 Hz), 4.83 (dd, 1H, J=5.61, 7.45 Hz),3.91 (q, 2H, J=5.4 Hz), 3.85-3.20(v br.s, 1H), 2.23 (m, 2H). Anal.Calc'd for C₁₇ H₁₈ N₂ O₃. 0.1 H₂ O: C 68.03, H 6.11, N 9.33. Found: C67.93, H 6.05, N 9.05.

REFERENCE EXAMPLE 66 Intermediate 10488-224-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared by methods F and G, alkylating with 3-chlorobenzyl bromide, in55% yield. The product was isolated as an oil which could becrystallized from Et₂ O/Hexane, mp 63°-67° C.; MS (Cl) MH⁺ 318; IR (KBr)3477, 2927, 2863, 1688, 1599, 1576, 1503, 1466, 1217, 1109, 931, 903cm⁻¹ ; ¹ H NMR (CDCl₃) 7.26 (m, 3H), 7.12 (m, 1H), 7.01 (m, 2H), 6.94(m, 1H), 6.82 (m, 1H), 5.15 (d, 1H, J=16.3 Hz), 5.08 (d, 1H, J=16.2 Hz),4.85 (dd, 1H, J=5.5, 7.6 Hz), 3.92 (d, 2H, J=4.9 Hz), 2.39-2.14 (br. m,3H). Anal. Calc'd for C₁₇ H₁₆ ClNO₃ : C 64.26, H 5.08, N 4.44. Found: C63.89, H 5.00, N 4.13.

REFERENCE EXAMPLE 67 Intermediate 11653-85-B-13,4-Dihydro-2-(2-hydroxyethyl)-7-nitro-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-23 (Reference Example 31) by methods Fand G, alkylating with 3-nitrobenzyl chloride, in 66% yield, mp157°-160° C.; MS (Cl) MH⁺ 374; IR (KBr) 3592, 3433, 3087, 2926, 2892,1671, 1598, 1525, 1482, 1433, 1219, 1168, 1097, 838 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 8.17 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.83 (d, 1H, J=2.5Hz), 7.65 (d, 1H, J=7.8 Hz), 7.58 (t, 1H, J=7.8 Hz), 7.08 (d, 1H, J=9.2Hz), 5.40 (d, 1H, J=16.5 Hz), 5.31 (d, 1H, J=16.6), 5.07 (dd, 1H, J=4.0,9.0 Hz), 4.57 (t, 1H, J=5.2 Hz), 3.80 (m, 2H), 2.23 (m, 1H), 2.10 (m,1H). Anal. Calc'd for C₁₇ H₁₅ N₃ O₇ : C 54.69, H 4.05, N 11.26. Found: C54.57, H 4.04, N 11.08.

REFERENCE EXAMPLE 68 Intermediate 11653-58C4-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-6-nitro-3-oxo-2H-benzoxazine

Prepared from intermediate 11653-33A (Reference Example 32) by methods Fand G, alkylating with 3-chlorobenzyl bromide, in 77% yield, mp >38° C.(dec); MS (Cl) MH⁺ 363; IR (KBr) 3855, 3745, 3423, 1686, 1590, 1522,1448, 1389, 1343, 1267, 1056, 875, 778, 680 cm⁻¹ ; ¹ H NMR (CDCl₃) δ7.93 (dd, 1H, J=2.5, 8.8 Hz), 7.78 (d, 1H, J=2.5 Hz), 7.30 (m, 3H), 7.19(m, 1H), 7.10 (d, 1H, J=8.8 Hz), 5.20 (d, 1H, J=16.3 Hz), 5.14 (d, 1H,J=16.2 Hz), 5.03 (dd, 1H, J=5.3, 7.6 Hz), 3.93 (t, 2H, J=6.2 Hz),2.41-2.19 (m, 2H), 1.71 (br s, 1H). Anal. Calc'd for C₁₇ H₁₅ ClN₂ O₅ : C56.29, H 4.17, N 7.72. Found: C 56.19, H 4.22, N 7.55.

REFERENCE EXAMPLE 69 Intermediate 11653-1423,4-Dihydro-2-(2-hydroxyethyl)-7-nitro-4-(2-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-23 (Reference Example 31) by methods Fand I, alkylating with 2-nitrobenzyl chloride, in 52% yield, mp139°-143° C.; MS (Cl) MH⁺ 374; IR (KBr) 3569, 3122, 3088, 2942, 2892,1693, 1600, 1530, 1501, 1420, 1390, 1254, 1059, 888, 727 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 8.24 (dd, 1H, J=1.2, 8.0 Hz), 7.90 (d, 1H, J=2.5 Hz), 7.83(dd, 1H, J=2.6, 8.9 Hz), 7.62 (m, 2H), 7.20 (d, 2H, J=8.9 Hz), 5.59 (d,1H, J=18.2 Hz), 5.49 (d, 1H, J=18.2 Hz), 5.16 (dd, 1H, J=4.4, 8.5 Hz),4.79 (t, 1H, J=5.2 Hz), 3.66 (m, 2H), 2.05 (m, 2H). Anal. Calc'd for C₁₇H₁₅ N₃ O₇ : C 54.69, H 4.05, N 11.26. Found: C 54.81, H 4.03, N 11.07.

REFERENCE EXAMPLE 70 Intermediate 11653-44A4-(2-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-6-nitro-3-oxo-2H-benzoxazine

Prepared from intermediate 11653-33A (Reference Example 32) by methods Fand G, alkylating with 2-chlorobenzyl chloride, in 23% yield, mp108°-110° C.; MS (Cl) MH⁺ 363; IR (KBr) 3520, 3092, 2984, 2938, 2889,1906, 1775, 1588, 1474, 1446, 1316, 1253, 1185, 1127, 1112, 926, 680cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.94 (dd, 1H, J=2.5, 8.8 Hz), 7.62 (d, 1H,J=2.5 Hz), 7.56 (d, 1H, J=7.6 Hz), 7.31 (m, 3H), 7.15 (d, 1H, J=7.3 Hz),5.25 (s, 2H), 5.16 (dd, 1H, J=4.2, 8.5 Hz), 4.78 (t, 1H, J=5.2 Hz), 3.63(m, 2H), 2.09 (m, 2H). Anal. Calc'd for C₁₇ H₁₅ ClN₂ O₅ : C 56.29, H4.17, N 7.72. Found: C 56.19, H 4.10, N 7.58.

REFERENCE EXAMPLE 71 Intermediate 11653-1733,4-Dihydro-2-(2-hydroxyethyl)-4-(4-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and I, alkylating with 4-nitrobenzyl chloride, in 89%yield, mp 124°-127° C.; MS (Cl) MH⁺ 329; IR (KBr) 3498, 3076, 2930,2863, 1656, 1605, 1500, 1466, 1302, 1279, 1184, 1126, 982, 613 cm⁻¹ ; ¹H NMR (CDCl₃) δ 8.20 (dd, 2H, J=2.0, 6.9 Hz), 7.40 (d, 2H, J=8.8 Hz),7.03 (m, 2H), 6.93 (m, 1H), 6.75 (d, 1H, J=7.6 Hz), 5.25 (s, 2H), 4.88(dd, 1H, J=5.4, 7.6 Hz), 3.93 (m, 2H), 2.38-2.17 (m, 2H), 2.10 (m, 1H).Anal. Calc'd for C₁₇ H₁₆ N₂ O₅ : C 62.19, H 4.91, N 8.54. Found: C62.05, H 4.87, N 8.39.

REFERENCE EXAMPLE 72 Intermediate 11653-170-A24-Benzyl-3,4-dihydro-2-(2-hydroxyethyl)-7-nitro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-23 (Reference Example 31) by methods Fand G, alkylating with benzyl bromide, in 98% yield, mp 102°-105° C.; MS(Cl) MH⁺ 329; IR (KBr) 3561, 3086, 3062, 2970, 2932, 2873, 1698, 1598,1500, 1452, 1075, 985 cm⁻¹ ; ¹ NMR (CDCl₃) δ 7.88 (d, 1H, J=2.5 Hz),7.82 (dd, 1H, J=2.5, 8.9 Hz), 7.34 (m, 3H), 7.23 (m, 2H), 6.96 (d, 1H,J=8.9 Hz), 5.23 (d, 1H, J=16.4 Hz), 5.17 (d, 1H, J=16.4 Hz), 4.80 (dd,1H, J=5.1, 7.9 Hz), 3.94 (m, 2H), 2.34 (m, 1H), 2.28 (m, 1H), 1.98 (t,1H, J=5.5 Hz). Anal. Calc'd for C₁₇ H₁₆ N₂ O₅ : C 62.19, H 4.91, 8.53.Found: C 61.81, H 4.63, N 8.36.

REFERENCE EXAMPLE 73 Intermediate 11653-174-A3,4-Dihydro-2-(2-hydroxyethyl)-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and I, alkylating with 2-nitrobenzyl chloride, in 43%yield, mp 128.5°-130° C.; MS (Cl) MH⁺ 329; IR (KBr) 3850, 3495, 3074,2974, 2949, 2896, 1658, 1605, 1576, 1515, 1503, 1468, 1426, 1362, 1218,1163, 902 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.20 (dd, 1H, J=1.3, 8.1 Hz), 7.67(t, 1H, J=7.6 Hz), 7.56 (t, 1H, J=7.0 Hz), 7.15 (d, 1H, J=7.0 Hz), 7.08(d, 1H, J=7.7 Hz), 6.99 (m, 1H), 6.92 (d, 2H, J=3.7 Hz), 5.49 (d, 1H,J=18.2 Hz), 5.42 (d, 1H, J=18.1 Hz), 4.94 (dd, 1H, J=4.1, 9.0 Hz), 4.72(t, 1H, J=5.2 Hz), 3.63 (m, 2H), 2.00 (m, 2H). Anal. Calc'd for C₁₇ H₁₆N₂ O₅ : C 62.19, H 4.91, N 8.53. Found: C 61.85, H 4.89, N 8.37.

REFERENCE EXAMPLE 74 Intermediate 10508-23-A4-Benzyl-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with benzyl chloride, in 49% overallyield and crystallized from ether/hexane to produce a white solid, mp83°-85.5° C.; IR (KBr) 3213, 1680, 1505, 1399, 1250, 1050, 753 cm⁻¹ ; ¹H NMR (CDCl₃) δ 2 .17-2.38 (m, 3H), 3.92 (q, J=5.7 Hz, 2H), 4.84 (dd,J=7.5, 5.6 Hz, 1H), 5.16 (s, 2H), 6.86-7.03 (m, 4H), 7.21-7.37 (m, 5H);MH⁺ at m/z=284; Anal. Calc'd for C.sub. 17H₁₇ NO₃ : C, 72.07; H, 6.05;N, 4.94. Found: C, 72.08; H, 6.20; N, 4.87.

REFERENCE EXAMPLE 75 Intermediate 10508-25-A3,4-Dihydro-2-(2-hydroxyethyl)-4-(2-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with the methanesulfonate ester of2-methoxybenzyl alcohol, in 47% overall yield as a light yellow gumafter flash chromatography, eluting with EtOAc/hexanes, IR (Neat) 3436,2941, 1583, 1683, 1501, 1466, 1403, 1281, 1246, 1113, 1052, 751 cm⁻¹ ; ¹H NMR (CDCl₃) δ 2.18-2.36 (m, 2H), 2.39 (br t, J=6.0 Hz, 1H), 3.90 (s,3H), 3.92 (br q, J=5.5 Hz, 2H), 4.85 (dd, J=7.4, 5.7 Hz, 1H), 5.15 (s,2H), 6.81-7.03 (m, 7H), 7.23 (td, J=8.3, 1.7 Hz, 1H); MH⁺ at m/z=314;Anal. Calc'd for C₁₈ H₁₉ NO₄.0.2 H₂ O: C, 68.21; H, 6.17; N, 4.42.Found: C, 68.36; H, 6.18; N, 4.36.

REFERENCE EXAMPLE 76 Intermediate 10508-22-A3,4-Dihydro-2-(2-hydroxyethyl)-4-(3-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine

Prepared by Methods F and G, alkylating with 3-methoxybenzyl chloride,in 49% overall yield as a clear viscous gum, after flash chromatographyeluting with 25-50% EtOAc in hexane, IR (Neat) 3433, 2941, 1683, 1583,1501, 1466, 1403, 1262, 1152, 1052, 753 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.17-2.37 (m, 3H), 3.77 (s, 3H), 3.91 (br q, J=5.3 Hz, 2H), 4.84 (dd,J=7.5, 5.6 Hz, 1H), 5.12 (ABq, J_(AB) =17 Hz, 2H), 6.76-7.03 (m, 7H),7.24 (td, J=7.6, 0.98 Hz, 1H); MH⁺ at m/z=314; Anal. Calc'd for C₁₈ H₁₉NO₄ : C, 68.99; H, 6.11; N, 4.47. Found: C, 68.54; H, 6.14; N, 4.33.

REFERENCE EXAMPLE 77 Intermediate 10508-82-A4-(3-Benzyloxybenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with the methanesulfonate ester of3-benzyloxybenzyl alcohol, in 67% overall yield as a viscous liquid,after flash chromatography eluting with 30-100% EtOAc in hexane, IR(CHCl₃) 3434, 2933, 1681, 1500, 1401, 1256, 1054, 751 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.77 (br s, 1H plus HDO), 2.20-2.34 (m, 2H), 3.91 (t, J=5.5Hz, 2H), 4.82 (dd, J=7.5, 5.7 Hz, 1H), 5.02 (s, 2H), 5.11 (ABq, J_(AB)=16.0 Hz, 2H), 6.85-7.01 (m, 7H), 7.22-7.41 (m, 6H); MH+ at m/z=390;Anal. Calc'd for C₂₄ H₂₃ NO₄ : C, 74.02; H, 5.95; N, 3.60. Found: C,73.61; H, 6.03; N, 3.55.

REFERENCE EXAMPLE 78 Intermediate 10508-84-A13,4-Dihydro-2-(2-hydroxyethyl)-4-(1-naphthylmethyl)-3-oxo-2H-1,4-benzoxazin

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 1-chloromethylnaphthalene, in 42%overall yield. The crude product was crystallized fromether/EtOAc/hexane to afford a white solid, mp 100°-104° C.; IR (KBr)3435, 2896, 1668, 1504, 1414, 1253, 1132, 1068, 768, 758 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.92 (br s, 1H Plus HDO), 2.26-2.44 (m, 2H), 3.96 (t, J=5.6Hz, 2H), 4.94 (dd, J=7.5, 5.6 Hz, 1H), 5.62 (ABq, J_(AB) =16.9 Hz, 2H),6.72 (dd, J=8.0, 1.1 Hz, 1H), 6.84 (td, J=8.1, 1.5 Hz, 1H), 6.96-7.11(m, 3H), 7.36 (t, J=7.4 Hz, 1H), 7.54-7.64 (m, 2H), 7.78 (d, J=8.2 Hz,1H), 7.92 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H); MH⁺ at m/z=334;Anal. Calc'd for C₂₁ H₁₉ NO₃ : C, 75.66; H, 5.74; N, 4.20. Found: C,75.56; H, 5.80; N, 4.14.

REFERENCE EXAMPLE 79 Intermediate 10508-80-13,4-Dihydro-2-(2-hydroxyethyl)-4-(2-naphthylmethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 2-chloromethyl naphthalene, in 81%overall yield. the crude product was crystallized from ether/hexane toafford a white solid, mp 81°-87° C.; IR (KBr) 3459, 2940, 1665, 1500,1403, 1277, 1242, 1066, 746 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.23-2.40 (m, 3H),3.95 (t, J=5.4 Hz, 2H), 4.90 (dd, J=7.6, 5.6 Hz, 1H), 5.32 (ABq, J_(AB)=16.1 Hz, 2H), 6.87-7.03 (m, 4H), 7.38 (d, J=8.5 Hz, 1H), 7.43-7.48 (m,2H), 7.67 (s, 1H), 7.75-7.84 (m, 3H); MH⁺ at m/z=334; Anal. Calc'd forC₂₁ H₁₉ NO₃ : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.71; N,4.02.

REFERENCE EXAMPLE 80 Intermediate 10508-794-(5-Chloro-2-thienylmethyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby Methods F and G, alkylating with 5-chloro-2-(chloromethyl)thiopheneand was isolated in 83% overall yield as a light yellow viscous oilafter flash chromatography using 30-50% EtOAc in hexane; IR (CHCl₃)3418, 2943, 1677, 1500, 1400, 1278, 1062, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.11-2.32 (m, 3H), 3.89 (q, J=5.4 Hz, 2H), 4.78 (dd, J=7.6, 5.5 Hz, 1H),5.15 (ABq, J_(AB) =16.0 Hz, 2H), 6.74 (d, J=3.7 Hz, 1H), 6.84 (d, J=3.7Hz, 1H), 7.01-7.08 (m, 4H); MH⁺ at m/z=324; Anal. Calc'd for C₁₅ H₁₄ClNO₃ S.0.25 H₂ O: C, 54.88; H, 4.45; N, 4.27; S, 9.77. Found: C, 54.86;H, 4.41; N, 4.04; S, 9.87.

REFERENCE EXAMPLE 81 Intermediate 11758-71-2 Methyl 4-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazin-4-yl!methylbenzoate

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 4-(methoxycarbonyl)benzyl chloride,to afford the alcohol as a white solid in 65% yield, mp=94°-95° C.; ¹ HNMR (CDCl₃) δ 8.00 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.95-7.04(m, 2H), 6.89 (dt, J=2.1, 8.0 Hz, 1H), 6.77 (dd, J=7.8, 1.5 Hz, 1H),5.20 (s, 2H), 4.86 (dd, J=5.4, 7.7 Hz, 1H), 3.82-3.96 (m, 5H with 3Hsinglet at δ 3.89), 2.16-2.37 (m, 3H, one of which is exchangeable). ¹³C NMR (CDCl₃) δ 166.8, 166.5, 144.1, 141.1, 130.1 (CH), 129.4, 128.4,126.3 (CH), 124.2 (CH), 122.8 (CH), 117.3 (CH), 115.2 (CH), 75.1 (CH),58.7 (CH₂), 52.0 (CH₃), 45.1 (CH₂), 33.1 (CH₂). IR 3450-3500 (br), 1719,1660 cm⁻¹. MS 342 (MH⁺), 324 (M--OH)⁺, 310 (M--OMe)⁺. Anal. Calc'd. forC₁₉ H₁₉ NO₅ : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.48; H, 5.47; N,3.97.

REFERENCE EXAMPLE 82 Intermediate 11758-93-2A Methyl 3-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazin-4-yl!methylbenzoate

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 3-(methoxycarbonyl)benzyl chloride,and isolated as a white powder in 87% yield, mp 73°-75° C.; ¹ H NMR(CDCl₃) δ 7.92-7.95 (m, 2H), 7.38-7.43 (m, 2H), 6.96-7.03 (m, 2H), 6.91(dt, J=2.3, 7.3 Hz, 1H), 6.81 (dd, J=1.4, 7.7 Hz, 1H), 5.23 (d, J=16.3Hz, 1H), 5.16 (d, J=16.3 Hz, 1H), 4.87 (dd, J=5.7, 7.4 Hz, 1H),3.92-3.95 (m, 2H), 3.91 (s, 3H), 2.21-2.37 (m, 3H containing oneexchangeable hydrogen). ¹³ C NMR (CDCl₃) δ 166.9, 166.7, 144.2, 136.5,130.9 (CH), 130.7, 129.1 (CH), 128.7 (CH), 128.5, 127.7 (CH), 124.3(CH), 122.9 (CH), 117.4 (CH), 115.4 (CH), 75.3 (CH), 58.9 (CH₂), 52.2(CH₂), 45.1 (CH₂), 33.3 (CH₂). IR 3569, 2948, 1709, 1676, 1502 cm⁻¹. MS342 (MH⁺). Anal. Calc'd. for C₁₉ H₁₉ NO₅ : C, 66.85; H, 5.61; N, 4.10.Found: C, 66.37; H, 5.62; N, 3.97.

REFERENCE EXAMPLE 83 Intermediate 11758-82-2 Ethyl 2-3,4-Dihydro-2-(2-hydroxyethyl)-3-oxo-2H-1,4-benzoxazin-4-yl!methylbenzoate

Prepared from2-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 2-(methoxycarbonyl)benzyl chloride,and isolated as a white solid in 38% yield overall, mp 114°-115.5° C.(EtOAc/Hexanes). ¹ H NMR (CDCl₃) δ 8.08 (dd, J=1.4, 7.8 Hz, 1H), 7.40(dt, J=1.3, 7.5 Hz, 1H), 7.33 (br t, J=7.6 Hz, 1H), 6.97-7.06 (m, 3H),6.89 (dt, J=1.9, 7.5 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.63 (d, J=18.0Hz, 1H), 5.54 (d, J=18.0 Hz, 1H), 4.88 (dd, J=5.7, 7.4 Hz, 1H), 4.41 (q,J=7.1 Hz, 2H), 3.90-3.95 (m, 2H), 2.23-2.35 (m, 2H), 1.43 (t, J=7.1 Hz,3H). IR 3450-3550 (br), 1675, 1502 cm⁻¹. MS 356 (MH⁺). Anal. Calc'd. forC₂₀ H₂₁ NO₅ : C, 67.59; H, 5.96; N, 3.94. Found: C, 67.29; H, 5.97; N,3.83.

REFERENCE EXAMPLE 84 Intermediate 11578-1904-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-2H-pyrido4,3-b!-1,4-oxazine

Freshly prepared 4-hydroxypyridine nitrate was nitrated by the procedureof D. Rasala and R. Gawinecki, Org. Prep. Proc. Int., 1985, 17, 409-423.An EtOH solution of this nitropyridine (1 eq) and NaOAc (1 eq) wasreduced with 10% Pd/C (10% w/w) under a hydrogen atmosphere at 50 psigfor 4 h. The crude 3-amino-4-hydroxypyridine was dissolved in DMF (5 mL)and treated with NaH (1.2 eq). This mixture was then treated withα-bromo-γ-butyrolactone (1.2 eq) at room temperature under nitrogen.After stirring at room temperature for 24 h, the DMF solution wastreated with imidazole (1.2 eq) and t-butyldimethylsilyl chloride (1.2eq). This solution was stirred for 16 h and then quenched with H₂ O. Theaqueous solution was extracted with EtOAc and the combined extract waswashed with H₂ O and dried over MgSO₄. The EtOAc solution was filteredthrough SiO₂ and concentrated under vacuum to afford the intermediatesilyloxy compound in 14% yield. This material was alkylated by Method F,with 3-chlorobenzyl bromide, and then deprotected with TFA (20% v/v) inCHCl₃ to afford the alcohol in 41% yield as a white crystalline solid;IR (KBr) 3519, 1664, 1393, 1320, 1192, 1082, 1054, 868 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 1.97-2.09 (m, 2H), 3.58-3.62 (m, 2H), 4.75 (t, J=5.0, 1H),5.10 (dd, J=8.5, 4.2 Hz, 1H), 5.21 (s, 2H), 7.07 (d, J=5.3 Hz, 1H), 7.25(br d, J=6.8 Hz, 1H), 7.35-7.43 (m, 3H), 8.13 (d, J=5.8 Hz, 1H), 8.20(s, 1H); MH+ at m/z=319.

REFERENCE EXAMPLE 85 Intermediate 11721-108-13,4-dihydro-2-(2-hydroxyethyl)-4-(3-thienylmethyl)!-3-oxo-2H-1,4-benzoxazine

Tributyl phosphine (1.5 eq) and 1,1'-(azodicarbonyl)dipiperidine (1.5eq) were added to a solution of2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine(1 eq) in CH₂ Cl₂ at room temperature. 3-thiophenemethanol (1.5 eq) wasadded dropwise and the mixture was stirred for 16 hours at roomtemperature. Hexane was added and this mixture was filtered andconcentrated in vacuo. The oily residue was purified by columnchromatography using 1-2% EtOAc/CH₂ Cl₂ as an eluent to give thealkylated intermediate as yellow oil; MH+ at m/z=404. The alkylatedintermediate was treated following the procedure of method G to give thetitle compound as a clear oil. IR (neat) 3427, 3101, 1681, 1500, 1060,750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.1-2.4 (m, 2H), 3.8-4.0 (m, 2H), 4.15 (q,1H), 4.80 (t, 1H), 5.21 (s, 2H), 7.07 (m, 5H), 7.1 (m, 1H), 7.25-7.3 (m,1H); MH+ at m/z=289.

REFERENCE EXAMPLE 86 Intermediate 11653-24A4-(2-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-7-nitro-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 2-chlorobenzyl bromide, to give ayellow solid: mp 106°-108° C.; MS (Cl) 363 (MH⁺); IR (KBr) 3268, 3122,3088, 3068, 2969, 2937, 2881, 1888, 1794, 1571, 1478, 1210, 1148, 1135,1116, 972, 926, 864, 705, 626, 475 cm⁻¹ ; ¹ H NMR (CDCl₃ /TMS) δ 7.90(d, 1H, J=2.42 Hz), 7.84 (dd, 1H, J=2.51, 8.91 Hz), 7.45 (d, 1H, J=7.77Hz), 7.20 (m, 2H), 6.95 (d, 1H, J=7.52 Hz), 6.81 (d, 1H, J=8.90 Hz),5.29 (s, 2H), 5.00 (dd, 1H, J=5.13, 7.90 Hz), 3.95 (q, 2H, J=5.51 Hz),2.30 (brm, 2H), 1.86 (t, 1H, J=5.47); Anal. Calc'd for C₁₇ H₁₅ ClN₂ O₅ :C 56.29, H 4.17, N 7.72. Found: C 56.25, H 4.24, N 7.60.

REFERENCE EXAMPLE 87 Intermediate 11653-35B4-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-3-oxo-7-nitro-2H-1,4-benzoxazine

Prepared from2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazineby methods F and G, alkylating with 3-chlorobenzyl bromide, to give ayellow solid: mp 100°-102.5° C.; MS (Cl) 363 (MH⁺); IR (KBr) 3512, 3092,3058, 2980, 2939, 2886, 1888, 1600, 1518, 1498, 1475, 1443, 1431, 1278,1204, 1107, 1080, 1020, 863, 681, 602, 452 cm⁻¹ ; ¹ H NMR (CDCl₃ /TMS) δ7.89(d, 1H, J=2.46 Hz), 7.84(dd, 1H, J=2.53, 8.84 Hz), 7.27(m, 3H),7.10(m, 1H), 6.90(d, 1H, J=8.85 Hz), 5.17(s, 2H), 4.99(dd, 1H, J=5.13,7.85 Hz), 3.94(m, 2H), 2.35(m, 1H), 2.24(m, 1H), 1.92(t, 1H, J=5.40 Hz);Anal. Calc'd for C₁₇ H₁₅ ClN₂ O₅ : C 56.29, H 4.17, N 7.72. Found: C56.25, H 4.09, N 7.63.

REFERENCE EXAMPLE 88 Intermediate 10840-117-13,4-Dihydro-2-(2-hydroxyethyl)-4-methyl-7-nitro-3-oxo-2H-1,4-benzoxazine

Prepared from intermediate 11653-23 (Reference Example 31) by methods Fand G, alkylating with methyl iodide, to give an oil: Anal. Calc'd forC₁₁ H₁₃ NO₃.9/10 H₂ O: C 62.14, H 6.41, N 6.59. Found: C 62.21, H 6.27,N 6.42

Compound 1 2- 2-4-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl!-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR22## Method J

Intermediate 10488-22 (7.65 g, 1 eq, Reference Example 66), wasdissolved in THF. Triphenylphosphine (0.5 g, 1.1 eq) and4-(N-t-butoxycarbonyl)aminomethylphenol (0.38 g, 1 eq) were added,followed by dropwise addition of diethyl azodicarboxylate (0.303 ml, 1.1eq). The reaction was stirred at reflux temperature for 48 h andconcentrated under vacuum. The residue was triturated with Et₂ O and theprecipitate removed by filtration. The product was isolated from thefiltrate by flash chromatography, eluting with EtOAc/hexanes. Fractionscontaining product were crystallized from EtOAc/hexanes to afford a 50%yield of a white powder, mp 99°-100° C.; IR (KBr) 3386, 2981, 1692,1613, 1501, 1393, 1366, 1248, 1171, 1053, 862, 752, 388 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 7.29-7.2 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 7.13 (m, 1H),7.04-6.91 (m, 3H), 6.88 (d, J=8.6 Hz, 2H), 6.82 (dd, J=8, 1.4 Hz), 5.17(d, J=16 Hz, 1H), 5.08 (d, J=16 Hz, 1H), 4.94 (dd, J=9.2, 4.0 Hz, 1H),4.75 (br s, 1H), 4.24 (m, 4H), 2.56 (m, 1H), 2.34 (m, 1H), 1.46 (s, 9H).Anal. Calc'd for C₂₉ H₃₁ ClN₂ O₅ : C 66.60, H 5.97, N 5.36. Found: C66.41, H 6.00, N 5.34.

Compound 2 2- 2-4-(Aminomethyl)phenoxy!ethyl!-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR23## Method K

Compound 1 was dissolved in isopropyl alcohol containing an excess ofHCl .sub.(g) (0.2-0.3 g/ml) and stirred at room temperature 2 h. Theproduct was filtered from the reaction mixture and the solid was washedwith Et₂ O to afford an 87% yield of a white solid, mp 194-200 (dec); MS(Cl) MH⁺ 422; IR (KBr) 2930, 1609, 1503, 1404, 1306, 1283, 1248, 1182,1111, 1051, 833 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.45-8.24 (br s, 2H), 7.42(d, 2H, J=8.6 Hz), 7.35 (m, 2H), 7.22 (d, 1H, J=6.8 Hz), 7.05 (m, 5H),5.23 (d, 1H, J=16.5 Hz), 5.13 (d, 1H, J=16.5 Hz), 5.00 (dd, 1H, J=4.2,8.6 Hz), 4.22 (m, 2H), 3.94 (br t, 2H, J=2.5 Hz), 3.39 (br s, 2H), 2.40(m, 1H), 2.25 (m, 1H). Anal. Calc'd for C₂₄ H₂₂ ClN₂ O₃.HCl: C 62.89, H5.06, N 6.11. Found: C 62.49, H 5.21, N 6.03.

Compound 3 2- 2-4-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR24##

Prepared by method J, using intermediate 10353-28-1, (Reference Example41) modified by stirring at room temperature for 48 h, in 54% yield as awhite solid, mp121°-122.5° C.; IR (KBr) 3400, 2977, 2931, 1690, 1613,1516, 1503, 1468, 1436, 1395, 1366, 1301, 1277, 1248, 1171, 1094, 1053,1014, 753 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.33-7.22 (m, 2H), 7.22-7.15 (m, 4H),7.03-6.8 (m, 6H), 5.16 (d, J=16.6 Hz, 1H), 5.08 (d, J=16.6 Hz, 1H), 4.92(dd, J=9.4, 4.1 Hz, 1H), 4.76 (br s, 1H), 4.25 (m, 4H), 2.57 (m, 1H),2.33 (m, 1H), 1.47 (s, 9H). Anal. Calc'd for C₂₉ H₃₁ ClN₂ O₅ : C 66.60,H 5.97, N 5.36. Found: C 66.48, H5.86, N 5.32.

Compound 4 2- 2-4-(Aminomethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR25##

Prepared by method K using Compound 3. The HCl/isopropanol solution wasevaporated under vacuum and the product isolated by crystallization fromCH₂ Cl₂ /Et₂ O in 76% yield as white solid, mp 200°-201° C.; IR (KBr)3480, 3360, 3235, 2910, 2878, 1681, 1609, 1519, 1503, 1465, 1401, 1281,1243, 1183, 1110, 1023, 913, 830, 797, 749, 569, 529 530 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 8.18 (br s, 3H), 7.40 (m, 4H), 7.30 (d, J=8.6 Hz, 2H), 7.02(m, 6H), 5.21 (d, J=16.8 Hz, 1H), 5.12 (d, J=16.8 Hz, 1H), 4.98 (dd,J=9.2, 4.4 Hz, 1H), 4.23 (m, 2H), 3.96 (m, 2H), 2.39 (m, 1H), 2.25 (m,1H). Anal. Calc'd for C₂₄ H₂₃ ClN₂ O₃ .HCl.0.5 H₂ O: C 61.54, H 5.38, N5.98. Found: C 61.30, H 5.33, N 5.90.

Compound 5 2- 2-4-(2-(t-Butoxycarbonylamino)ethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR26## Method L

The alcohol intermediate 10353-28-1 (0.6 g, 1 eq Reference Example 41)was dissolved in dry benzene (6 ml) and treated with tributylphosphine(0.63 ml, 1.5 eq) and boc-protected 4-(2-aminoethyl)phenol (0.66 g, 1.5eq). The resulting solution was cooled in an ice bath and1,1'-(azodicarbonyl)dipiperidine (ADDP, 0.71 g, 1.5 eq) was added in oneportion. The reaction was warmed to room temperature after 10 min. After20 h, diluted with Et₂ O and the white precipitate was filtered off. Thefiltrate was washed with 2N NaOH and concentrated. The product wasisolated by flash chromatography eluting with acetone/hexanes.Recrystallization from EtOAc/hexanes afforded a 72% yield of the productas a white solid 108°-109° C.; MS (Cl) 537 (MH⁺); IR (KBr) 3378, 2979,1798, 1609, 1515, 1500, 1395, 1368, 1246, 1171, 1061, 816, 749 cm⁻¹ ; ¹H NMR (CDCl₃) δ 7.39 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.11 (d,J=8.7 Hz, 2H), 7.04-6.80 (m, 4H), 6.86 (d, J=8.7 Hz, 2H), 5.14 (d,J=16.4 Hz, 1H), 5.11 (d, J=16.4 Hz, 1H), 4.93 (dd, J=9.5, 4.1 Hz, 1H),4.52 (br s, 1H), 4.23 (m, 2H), 3.34 (m, 2H), 2.74 (apparent t, J=7.1 Hz,2H), 2.56 (m, 1H), 2.33 (m, 1H), 1.44 (s, 9H). Anal. Calc'd for C₃₀ H₃₃ClN₂ O₅ : C 67.09, H 6.19, N 5.22. Found: C 66.88, H 6.07, N 5.22.

Compound 6 2- 2-4-(2-Aminoethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR27##

Prepared by method K using Compound 5. The HCl/isopropanol solution wasevaporated under vacuum after 18 h and the product isolated bycrystallization from CH₂ Cl₂ /Et₂ O in 43% yield as white solid, mp174-176° C.; IR (KBr) 3415, 2933, 1681, 1609, 1503, 1465, 1401, 1279,1241, 1065, 824, 789, 488, 428, 415 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.74 (brs, 3H), 7.39 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 7.1 (m, 4H), 6.93 (d, J=8.8 Hz, 2H), 5.20 (d, J=16.8 Hz, 1H),5.13 (d, J=16.8 Hz, 1H), 4.97 (dd, J=9.2, 4.1 Hz, 1H), 4.19 (m, 2H),2.99 (m, 2H), 2.80 (m, 2H), 2.38 (m, 1H), 2.24 (m, 1H). Anal. Calc'd forC₂₅ H₂₅ ClN₂ O₃.HCl: C 63.43, H 5.54, N 5.92. Found: C 63.17, H 5.47, N5.82.

Compound 7 2-{2-3-(2-t-Butoxycarbonylaminoethyl)phenoxy!ethyl}-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR28##

Prepared by method J using intermediate 10353-28-1 (Reference Example41), modified by stirring at room temperature for 20 h, in 30% yield asa white solid; mp 97°-98.5° C.; IR (KBr) 3368, 3066, 3050, 2981, 2940,1680, 1602, 1594, 1522, 1503, 1466, 1447, 1399, 1364, 1267, 1175, 1113,1052, 1013 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.32-7.16 (m, 5H), 7.05-6.89 (m,3H), 6.86-6.73 (m, 4H), 5.16 (d, J=17.6 Hz), 5.09 (d, J=17.6 Hz), 4.93(dd, J=6.7, 5.0 Hz), 4.55 (m, 1H), 4.23 (m, 2H), 3.38 (m, 2H), 2.78(apparent t, J=7.2 Hz, 2H), 2.58 (m, 1H), 2.33 (m, 1H), 1.43 (s, 9H).Anal. Calc'd for C₃₀ H₃₃ ClN₂ O₅ : C 67.09, H 6.19, N 5.22. Found:C67.14, H 6.21, N 5.16.

Compound 8 2- 2-3-(2-Aminoethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR29##

Prepared by method K using Compound 7. The HCl/isopropanol solution wasevaporated under vacuum after 2.5 h and the product isolated bycrystallization from CH₂ Cl₂ /Et₂ O in ˜72% yield as a white solid, mp155°-156° C.; IR (KBr) 3400, 3052, 2940, 1683, 1605, 1501, 1399, 1301,1248, 1162, 1094, 1053, 751 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.40 (d, J=8.4Hz, 2H), 7.35-7.23 (m, 3H), 7.02 (m, 4H), 6.86 (m, 3H), 5.2 (d, J=17.0Hz, 1H), 5.14 (d, J=17 Hz, 1H), 5.15-3.30 (v br s, 4H), 4.22 (m, 2H),3.05 (m, 2H), 2.83 (m, 2H), 2.40 (m, 1H), 2.25 (m, 1H). Calc'd for C₂₅H₂₅ ClN₂ O₃.C₂ H₂ O₄.0.75 H₂ O: C 60.00, H 5.32, N 5.18. Found: C 60.11,H 5.08, N 5.06.

Compound 9 2- 2-3-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR30##

Prepared by method J, using intermediate 10353-28-1 (Reference Example41) and modified by stirring at room temperature for 24 h, in 50% yield.Trituration with hot Et₂ O afforded a white solid, mp 114°-116° C.; IR(KBr) 3365, 2985, 1686, 1600, 1526, 1503, 1451, 1395, 1366, 1268, 1173,1129, 1067, 1052, 843, 787, 760 cm⁻¹ ; 1H NMR (CDCl₃) δ 7.29 (d, J=8.9Hz, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.9 Hz, 2H), 7.15-6.78 (m,7H), 5.15 (d, J=16.8 Hz, 1H), 5.1 (d, J=16.8 Hz, 1H), 4.93 (dd, J=9.2,4.2 Hz, 1H), 4.82 (br s, 1H), 4.37-4.13 (m, 4H), 2.57 (m, 1H), 2.34 (m,1H), 1.46 (s, 9H). Anal. Calc'd for C₂₉ H₃₁ ClN₂ O₅ : C 66.60, H 5.97, N5.36. Found: C 66.62, H 5.90, N 5.33.

Compound 10 2- 2-3-(Aminomethyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR31##

Prepared by method K, using Compound 9. The HCl/isopropanol solution wasevaporated under vacuum after 24 h and the product isolated in 30% yieldby conversion to the oxalate salt followed by trituration with hot CH₂Cl₂. mp 127°-129° C.; IR (KBr) 3446, 3053, 1501, 1466, 1401, 1248, 797,747, 700, 486, 428 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.20 (br s, 1H), 7.40 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 5.21 (d,J=17.2 Hz, 1H), 5.13 (d, J=17.2 Hz, 1H), 4.98 (dd, J=9.2, 4.2, 1H),5.15-4.10 (v br s, 3H), 4.22 (m, 2H), 4.01 (s, 2H), 2.45 (m, 1H), 2.27(m, 1H). Calc'd for C₂₄ H₂₃ ClN₂ O₃.C₂ H₂ O₄.1.5 H₂ O: C 57.83, H 5.23,N 5.19. Found: C 58.06, H 4.85, N 5.20.

Compound 11 2- 2-3-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR32##

Prepared by method J, using intermediate 9086-189-1 (Reference Example42), without chromatography. The product was isolated by precipitationfrom aqueous methanol and made basic by dropwise addition of 2N NaOH,followed by recrystallization from MeOH/water, in 84% yield mp 115°-116°C.; MS (Cl) 523 (MH⁺); IR (KBr) 3357, 2979, 1686, 1611, 1586, 1526,1505, 1466, 1449, 1395, 1368, 1285, 1252, 1165, 1052, 749 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 7.43 (dd, J=7.6, 1.7 Hz, 1H), 7.27-7.13 (m, 4H), 7.16-6.96 (m,3H), 6.95-6.81 (m, 3H), 6.73 (dd, J=8.4, 1.3 Hz, 1H), 5.28 (d, J=17.8Hz, 1H), 5.21 (d, J=17.8 Hz, 1H), 4.97 (dd, J=9.4, 4.2 Hz, 1H), 4.82 (brs, 1H), 4.35-4.17 (m, 4H), 2.59 (m, 1H), 2.37 (m, 1H), 1.47 (s, 9H).Anal. Calc'd for C₂₉ H₃₁ ClN₂ O₅ : C 66.60, H 5.97, N 5.36. Found: C66.59, H 5.87, N 5.30.

Compound 12 2- 2-3-(Aminomethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine ##STR33##

Prepared by method K, using Compound 11. The HCl/isopropanol solutionwas evaporated under vacuum after 20 h and the product isolated bycrystallization from CH₂ Cl₂ in 50% yield as a white powder; mp191°-193° C.; MS (Cl) 423 (MH⁺); IR (KBr) 3419, 2889, 2624, 1683, 1605,1505, 1466, 1443, 1403, 1324, 1279, 1181, 1110, 1086, 1038, 951, 930,893, 791, 749, 695, 627, 567, 452 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.35 (br s,3H), 7.53 (dd, J=7.7, 1.2 Hz, 1H), 7.32 (m, 3H), 7.17 (s, 1H), 7.13-6.95(m, 6H), 6.85 (dd, J=7.7, 1.2 Hz, 1H), 5.22 (d, J=17.3 Hz, 1H), 5.13 (d,J=17.3 Hz, 1H), 5.04 (dd, J=8.8, 4.2 Hz, 1H), 4.25 (m, 2H), 4.0 (s, 2H),2.44 (m, 1H), 2.30 (m, 1H). Anal. Calc'd for C₂₄ H₂₃ ClN₂ O₃.HCl.0.5 H₂O: C 61.54, H 5.38, N 5.98. Found: C 61.35, H 5.08, N 5.87.

Compound 13 2- 2-4-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR34##

Prepared by method J using intermediate 9086-189-1 (Reference Example42), in 50% yield as a white solid, mp 121°-123° C.; IR (KBr) 3345,2979, 2925, 1683, 1611, 1503, 1466, 1401, 1248, 1171, 749 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 7.42 (dd, J=7.8, 1.4 Hz, 1H), 7.27-7.12 (m, 2H), 7.21 (d,J=8.4 Hz, 2H), 7.05-6.87 (m, 4H), 6.88 (d, J=8.4 Hz, 2H), 6.71 (d, J=7.8Hz, 1H), 5.27 (d, J=17.6 Hz, 1H), 5.21 (d, J=17.6 Hz, 1H), 4.96 (dd,J=9.4, 4.1 Hz, 1H), 4.76 (br s, 1H), 4.25 (m, 4H), 2.58 (m, 1H), 2.36(m, 1H), 1.46 (s, 9H). Anal. Calc'd for C₂₉ H₃₁ ClN₂ O₅ : C 66.60, H5.97, N 5.36. Found: C 66.35, H 5.82, N 5.72.

Compound 14 2- 2-4-(Aminomethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR35##

Prepared by method K from Compound 13. The isopropanol was removed undervacuum and the product isolated by crystallization from CHCl₃ /EtOAc in69% yield as a white solid; mp 200°-205° C.; MS (Cl) 423 (MH⁺); IR (KBr)3430, 2960, 2890, 2600, 1690, 1611, 1517, 1501, 1468, 1401, 1279, 1250,1183, 1050, 749, 407 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.22 (br s, 3H), 7.53(dd, J=7.6, 1.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.37-7.23 (m, 3H),7.12-6.95 (m, 4H), 7.02 (d, J=8.7 Hz, 2H), 6.83 (dd, J=7.9, 1.6 Hz, 1H),5.2 (d, J=17.2 Hz, 1H), 5.13 (d, J=17.2 Hz, 1H), 5.04 (dd, 8.4, 4.2 Hz,1H), 4.25 (m, 2H), 3.95 (s, 2H), 2.42 (m, 1H), 2.39 (m, 1H). Anal.Calc'd for C₂₄ H₂₃ ClN₂ O₃.HCl.0.3 H₂ O: C 62.02, H 5.34, N 6.03. Found:C 61.99, H 5.20, N 5.87.

Compound 15 2- 2-3-(2-(t-Butoxycarbonylamino)ethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR36##

Prepared by method J using intermediate 9086-189-1 (Reference Example42), in 48% yield as a white powder, mp 61°-65° C. (softens) 68°-70° C.;MS (Cl) 537 (MH⁺); IR (KBr) 3365, 2998, 2935, 1690, 1607, 1503, 1447,1401, 1366, 1254, 1171, 1050, 751 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.42 (dd,J=7.6, 1.2 Hz, 1H), 7.35-7.13 (m, 3H), 7.08-6.87 (m, 4H), 6.85-6.68 (m,4H), 5.28 (d, J=17.6 Hz, 1H), 5.21 (d, J=1H), 4.97 (dd, J=9.2, 4.1 Hz,1H), 4.54 (br s, 1H), 4.25 (m, 2H), 3.37 (m, 2H), 2.66 (m, 2H), 2.59 (m,1H), 2.38 (m, 1H), 1.44 (s, 9H). Anal. Calc'd for C₃₀ H₃₃ ClN₂ O₅ : C67.09, H 6.19, N 5.22. Found: C 67.08, H 6.15, N 5.17.

Compound 16 2- 2-3-(2-Aminoethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR37##

Prepared by method K using Compound 15. The isopropanol was removedunder vacuum after 3 h and the product isolated by crystallization fromCHCl₃ /EtOAc in 91% yield to afford a white solid, mp 173°-175° C.; MS(Cl) 437 (MH⁺); IR (KBr) 3420, 2932, 1687, 1603, 1501, 1466, 1445, 1401,1326, 1252, 1160, 1050,748, 695 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.94 (br s,3H), 7.53 (d, J=7.9 Hz, 1H), 7.37-7.23 (m, 3H), 7.15-6.95 (m, 5H), 6.86(m, 3H), 5.22 (d, J=17.5 Hz, 1H), 5.13 (d, J=17.5 Hz, 1H), 5.04 (dd,J=9.2, 2.2 Hz, 1H), 4.23 (m, 2H), 3.04 (m, 2H), 2.35 (m, 2H), 2.4 (m,1H), 2.29 (m, 1H). Anal. Calc'd for C₂₅ H₂₅ ClN₂ O₃.HCl.0.2 H₂ O: C62.95, H 5.58, N 5.87. Found: C 62.83, H 5.29, N 5.62.

Compound 17 2- 2-4-(2-(t-Butoxycarbonylamino)ethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR38##

Prepared by method J using intermediate 9086-189-1 (Reference Example42) in 33% yield as a white powder, mp 108°-111° C.; IR (KBr) 3378,2978, 2920, 1692, 1611, 1515, 1503, 1397, 1366, 1248, 1175, 1056, 751cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.43 (dd, J=8.0, 1.3 Hz, 1H), 7.26-7.13 (m,2H), 7.11 (d, J=8.5 Hz, 2H), 7.06-6.88 (m, 4H), 6.88 (d, J=8.5 Hz, 2H),6.71 (d, J=8.0 Hz, 1H), 5.28 (d, J=17.8 Hz, 1H), 5.22 (d, J=17.9 Hz,1H), 4.97 (dd, J=9.7, 4.2 Hz, 1H), 4.52 br s, 1H), 4.25 (m, 2H), 3.35(m, 2H), 2.74 (apparent t, J=7.1 Hz, 2H), 2.05 (m, 1H), 2.36 (m, 1H),1.44 (s, 9H). Anal. Calc'd for C₃₀ H₃₃ ClN₂ O₅ : C 67.09, H 6.19, N5.22. Found: C 66.71, H 6.00, N 5.58.

Compound 18 2- 2-4-(2-Aminoethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR39##

Prepared by method K using Compound 18. The isopropanol was removedunder vacuum after 1 h and the product isolated, by trituration with Et₂O, in 49% yield as an off white powder mp 143°-148° C.; MS (Cl) 437 (MH⁺-H₂ O); IR (KBr) 3365, 2930, 1686, 1609, 1515, 1503, 1468, 1445, 1401,1252, 1111, 1050, 826, 747 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.97 (br s, 3H),7.54 (dd, J=7.7, 1.4 Hz, 1H), 7.37-7.22 (m, 2H), 7.19 (d, J=8.6 Hz, 2H),7.12-6.95 (m, 4H), 6.94 (d, J=8.6 Hz, 2H), 6.83 (dd, J=7.6, 1.5 Hz, 1H),5.20 (d, J=17.3 Hz, 1H), 5.13 (d, J=17.3 Hz, 1H), 5.04 (dd, J=9.1, 4.0Hz, 1H), 4.21 (m, 2H), 2.99 (m, 2H), 2.82 (m, 2H), 2.40 (m, 1H), 2.27(m, 1H). Anal. Calc'd for C₂₅ H₂₅ ClN₂ O₃.HCl.0.5H₂ O: C 62.24, H 5.64,N 5.81. Found: C 62.17, H 5.31, N 6.13.

Compound 19 4-(2-Chlorobenzyl)-2- 2-4-(guanidinomethyl)phenoxy!ethyl!-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR40##

Prepared by method L using intermediate 9086-189-1 (Reference Example42) and N,N'-di-t-butoxycarbonyl-(4-hydroxyphenyl)methylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by dissolving the crude productresidue in aqueous methanol and treating with a dropwise addition of 2NNaOH until basic. The product oiled out of solution and removal ofsolvent by decantation afforded a viscous oil which was dried undervacuum and used without further purification. The deprotection stepafforded the product, after crystallization in CH₂ Cl₂, in 71% overallyield as a white powder, mp 180°-182° C.; MS (Cl) 465 (MH⁺); IR (KBr)3320, 3162, 1685, 1665, 1611, 1515, 1503, 1468, 1447, 1401, 1333, 1302,1281, 1243, 1181, 1113, 1048, 824, 749, 687, 565, 428, 401 cm⁻¹ ; ¹ HNMR (DMSO-d₆) δ 8.07 (br t, J=5.9 Hz, 1H), 7.53 (dd, J=8.0 Hz, 1H),7.8-6.7 (v br s, 4H), 7.35-7.15 (m, 3H), 7.26 (d, J=9.0 Hz, 2H),7.1-6.93 (m, 3H), 6.99 (d, J=9.0 Hz, 2H), 5.22 (d, J=17.9 Hz, 1H), 5.11(d, J=17.9 Hz, 1H), 5.04 (dd, J=8.8, 4.2 Hz, 1H), 4.3 (apparent d, J=6Hz, 2H), 4.23 (m, 2H), 2.41 (m, 1H), 2.28 (m, 1H). Anal. Calc'd for C₂₅H₂₅ ClN₄ O₃.HCl: C 59.89, H 5.23, N 11.17. Found: C 59.57, H 5.13, N10.99.

Compound 20 4-(2-Chlorobenzyl)-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR41##

Prepared by method L using intermediate 9086-189-1 (Reference Example42) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated, after flash chromatography andcrystallization, in 36% yield. The deprotected product was isolated asthe carbonate salt (tan solid) in 88% yield; mp 90° C. (dec); MS (Cl)479 (MH⁺); IR (KBr) 3600, 3350, 2939, 1688, 1515, 1501, 1401, 1243,1111, 1050, 834, 749, 522 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.53 (dd, J=7.8,1.6 Hz, 1H), 7.33 (dd, J=7.8, 1.6 Hz, 1H), 7.29 (m, 1H), 7.25 (dd, 7.4,1.6 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.12-6.93 (m, 4H), 6.9 (d, J=8.2Hz, 2H), 6.82 (dd, J=7.4, 1.6 Hz, 1H), 5.21 (d, J=17.2 Hz, 1H), 5.11 (d,J=17.2 Hz, 1H) 5.2 (dd, J=8.5, 4.1 Hz, 1H), 4.2 (m, 2H), 3.7-2.8 (br s,5H), 2.69 (m, 2H), 2.4 (m, 1H), 2.25 (m, 1H). Anal. Calc'd for C₂₆ H₂₇N₄ O₃ Cl .H₂ CO₃.0.3 H₂ O: C 59.35, H 5.46, N 10.25, Cl 6.49. Found: C59.37, H 5.29, N 10.25, Cl 6.86.

Compound 21 4-(4-Chlorobenzyl)-2- 2-4-(guanidinomethyl)phenoxy!ethyl!-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR42##

Prepared by method L using intermediate 10353-28-1 (Reference Example41) and N,N'-di-t-butoxycarbonyl-(4-hydroxyphenyl)methyl guanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by dissolving the crude productresidue in aqueous methanol and treating with a dropwise addition of 2NNaOH until basic. The product precipitated out of solution and wascollected by filtration. The resulting white solid was air dried andused without further purification. The deprotected product was isolatedas the carbonate salt (tan solid) in 24% overall yield as a tan solid,mp 90° C. (dec); MS (Cl) 465 (MH⁺); IR (KBr) 3330, 2940, 1685, 708,1650, 1600, 1513, 1501, 1466, 1399, 1302, 1279, 1245, 1177, 1094, 1052,799, 751 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.5-3.0 (v br s, 5H), 7.40 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 7.1-6.95 (m,4H), 6.91 (d, J=8.8 Hz, 2H), 5.21 (d, J=17.4 Hz, 1H) 5.13 (d, J=17.4 Hz,1H), 4.97 (dd, J=9.0, 4.2 Hz, 1H), 4.28 (m, 2H), 2.37 (m, 1H), 2.23 (m,1H). Anal. Calc'd for C₂₅ H₂₅ ClN₄ O₃.CH₂ O₃.0.3 H₂ O: C 58.66, H 5.23,N 10.52. Found: C 58.38, H 4.86, N 10.61.

REFERENCE EXAMPLE 89 Intermediate 10353-764-(2-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-2H-1,4-benzoxazine

Method M

Intermediate 9086-189-1 (1 g, 1 eq, Reference Example 42) was dissolvedin THF (5 ml) and treated with 1M Borane/THF (6.3 ml, 3 eq), and heatedto reflux. After 3 h, the reaction mixture was concentrated under vacuumand the residue was partitioned between Et₂ O and 1N HCl. The organiclayer was washed with saturated Na₂ CO₃, brine, dried over Na₂ SO₄ andconcentrated under vacuum. The product was isolated by flashchromatography, eluting with EtOAc/hexanes, to afford a 96% yield of acolorless oil.

REFERENCE EXAMPLE 90 Intermediate 10353-824-(3-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-2H-1,4-benzoxazine

Prepared by Method M, from intermediate 10488-22 (Reference Example 66),and isolated in 99% yield.

REFERENCE EXAMPLE 91 Intermediate 10353-834-(4-Chlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-2H-1,4-benzoxazine

Prepared by Method M from intermediate 10353-28-1 (Reference Example 41)and isolated in quanitative yield as a colorless oil.

REFERENCE EXAMPLE 92 Intermediate 10840-453,4-Dihydro-2-(2-hydroxyethyl)-4-(4-methylbenzyl)-2H-1,4-benzoxazine

Prepared by Method M from intermediate 10840-33 (Reference Example 46)in 80% yield and isolated as a green oil, IR (neat) 3371, 2921, 1607,1500, 1247, 1221, 1052, 743 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.77-2.00 (m, 3H),2.33 (s, 3H), 3.19 (dd, J=11.8, 7.7 Hz, 1H), 3.27 (dd, J=11.7, 2.6 Hz,1H), 3.86-3.94 (m, 2H), 4.33-4.40 (m, 1H), 4.40 (s, 2H), 6.60-6.71 (m,2H), 6.76-6.84 (m, 2H), 7.15 (br q, J_(AB) =8.2 Hz, 4H); Anal. Calc'dfor C₁₈ H₂₁ NO₂.0.6H₂ O: C, 73.49; H, 7.61; N, 4.76. Found: C, 73.33; H,7.22; N, 4.84.

REFERENCE EXAMPLE 93 Intermediate 10840-463,4-Dihydro-2-(2-hydroxyethyl)-4-(3-methoxybenzyl)-2H-1,4-benzoxazine

Prepared by Method M from 10508-22-A (Reference Example 76) inquantitative yield and isolated as a green oil, IR 3350, 2948, 1605,1505, 1283, 1262, 1050, 743 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.50-2.10 (v br s,1H), 1.78-2.01 (m, 2H), 3.20 (dd, J=11.7, 7.8 Hz, 1H), 3.28 (dd, J=11.7,2.6 Hz, 1H), 3.78 (s, 3H), 3.88 (t, J=5.6 Hz, 2H), 4.34-4.43 (m, 1H),4.40 (s, 2H), 6.62-6.79 (m, 2H), 6.76-6.89 (m, 5H), 7,24 (t, J=7.7 Hz,1H); MH⁺ at m/z=300; Anal. Calc'd for C₁₈ H₂₁ NO₃.0.2H₂ O; C, 71.36; H,7.12; N, 4.62. Found: C, 71.25; H, 7.00; N, 4.62.

REFERENCE EXAMPLE 94 Intermediate 10840-84-(2,4-Dichlorobenzyl)-3,4-dihydro-2-(2-hydroxyethyl)-2H-1,4-benzoxazine

Prepared by Method M from 10005-181-1 (Reference Example 48) in 87%yield and was isolated as a colorless oil. IR (neat) 3348, 1607, 1501,1247, 1221, 1046, 743 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.80-2.03 (m, 3H),3.27-3.37 (m, 2H), 3.85-3.98 (m, 2H), 4.38-4.45 (m, 1H), 4.45 (s, 2H),6.44 (dd, J=8.0, 1.4 Hz, 1H), 6.65 (td, J=7.6, 1.5 Hz, 1H), 6.77 (td,J=7.8, 1.6 Hz, 1H), 6.83 (dd, J=7.8, 1.6 Hz, 1H), 7.15-7.25 (m, 2H),7.42 (d, J=1.8 Hz); MH⁺ at m/z=338; Anal. Calc'd for C₁₇ H₁₇ Cl₂ NO₂ ;C, 60.37; H, 5.07; N, 4.14. Found: C, 60.04; H, 4.98; N, 4.05.

Compound 22 4-(4-Chlorobenzyl)-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3,4-dihydro-2H-1,4-benzoxazine##STR43##

Prepared by method L using intermediate 10353-83 (Reference Example 91)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated with satisfactory purity byflash chromatography (eluting with EtOAc/hexanes) in 58% yield. Thedeprotected product was isolated as the carbonate salt in 50% yield as atan solid, single homogeneous peak by HPLC (PDA detection) 15 cm C18column, eluting with 55/45 H₂ O (5% NH₄ OH, 5% HOAC)/CH₃ CN; MS (Cl) 466(MH⁺); IR (KBr) 3475, 3321, 3064, 2931, 2875, 1698, 1638, 1608, 1581,1513, 1502, 1467, 1696, 1358, 1303, 1288, 1244, 1178, 1116, 1047, 1013,833, 743 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.30-7.50 (br s, 2H), 7.40 (d, J=8.2Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 6.90 (d, J=8.2Hz, 2H), 6.77-6.60 (m, 3H), 6.55 (m, 1H), 4.53 (d, J=16.8 Hz, 1H), 4.45(d, J=16.8 Hz, 1H), 4.35 (m, 1H), 4.12 (br d, J=11.4 Hz, 2H), 3.60-3.10(br s, 5H), 3.49 (m, 2H), 2.73 (m, 2H), 2.05 (m, 2H).

Compound 23 4-(3-Chlorobenzyl)-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3,4-dihydro-2H-1,4-benzoxazine##STR44##

Prepared by method L using intermediate 10353-82 (Reference Example 90)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by flash chromatography (elutingwith EtOAc/hexanes) in 94% yield. The deprotected product was isolatedas the carbonate salt in 59% yield as a tan solid, single homogeneouspeak by HPLC (PDA detection) 15 cm C₁₈ column, eluting with 55/45 H₂ O(5% NH₄ OH, 5% HOAC)/CH₃ CN; MS (Cl) 466 (MH⁺); IR (KBr) 3473, 3316,3064, 2931, 2876, 1698, 1638, 1608, 1580, 1512, 1503, 1468, 1431, 1393,1359, 1303, 1243, 1221, 1178, 833, 742 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ8.50-7.60 (br s, 2H), 7.42-7.20 (m, 4H), 7.19 (d, J=7.7 Hz, 2H), 6.90(d, J=7.7 Hz, 2H), 6.78-6.70 (m, 3H), 6.58 (m, 1H), 4.55 (d, J=17.3 Hz,1H), 4.48 (d, J=17.3 Hz, 1H), 4.15 (m, 2H), 3.80-3.10 (br s, 4H), 3.52(br d, J=11.8 Hz, 2H), 3.25 (m, 2H), 2.73 (m, 2H), 2.08 (m, 2H).

Compound 24 4-(3-Chlorobenzyl)-3,4-dihydro-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-6-methyl-3-oxo-2H-1,4-benzoxazine##STR45##

Prepared by method L using intermediate 12168-10-1 (Reference Example39) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by flash chromatography (elutingwith EtOAc/hexanes) in ˜70% yield. The deprotected product wastriturated from Et₂ O dissolved in CH₂ Cl₂ and the solvent removed undervacuum to afford the product in 92% yield as a pale yellow solid, MS(Cl) 493 (MH⁺); IR (KBr) 3148, 1666, 1610, 1511, 1433, 1384, 1302, 1244,1178, 1112, 1052, 817, 772, 680, 527 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.50 (brt, J=5.7 Hz, 1H), 7.40-6.85 (v br s, 5H), 7.35 (m, 3H), 7.20 (m, 3H),6.94 (m, 4H), 6.81 (d, J=8.9 Hz, 1H), 5.20 (d, J=17.3 Hz, 1H), 5.12 (d,J=17.3 Hz, 1H), 4.94 (dd, J=9.1, 4.3 Hz, 1H), 4.18 (m, 2H), 3.31 (m,2H), 2.72 (apparent t, J=7.3 Hz, 2H), 2.37 (m, 1H), 2.30-2.13 (m, 1H),2.19 (s, 3H). Anal. Calc'd for C₂₇ H₂₉ ClN₄ O₃.HCl.1.0 H₂ O: C 59.23, H5.89, N 10.23. Found: C 59.47, H 5.60, N 10.11.

Compound 25 4-(3-Chlorobenzyl)-3,4-dihydro-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3-oxo-2H-pyrido 3,2-b!-1,4-oxazine##STR46##

Prepared by method L using intermediate 10353-191-1 (Reference Example40) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by flash chromatography (elutingwith EtOAc/hexanes) in 77% yield. The deprotected product was isolatedin 50% yield after trituration with Et₂ O, mp 47°-54° C. (softens)54°-56° C.; MS (Cl) 480 (MH⁺); IR (KBr) 3326, 3150, 1666, 1599, 1513,1459, 1398, 1331, 1278, 1229 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.0 (dd, J=4.9,1.4 Hz, 1H), 7.53 (br t, J=7.3 Hz, 1H), 7.47 (dd, J=7.9, 1.2 Hz, 1H),7.37 (s, 1H), 7.35-7.22 (m, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.09 (dd,J=7.9, 4.8 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 5.24 (d, J=16.3, Hz, 1H),5.23 (d, J=16.3 Hz, 1H), 5.12 (dd, J=8.2, 4.2 Hz, 1H), 4.15 (m, 2H),6.32 (m, 2H), 2.71 (m, 2H), 2.39 (m, 1H), 2.29 (m, 1H). Anal. Calc'd forC₂₅ H₂₆ ClN₅ O₃.2HCl.0.8 H₂ O: C 56.57, H 5.43, N 13.19. Found: C 56.84,H 5.65, N 13.04.

Compound 26 4-(4-Chlorobenzyl)-3,4-dihydro-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3-oxo-2H-1,4-benzoxazine ##STR47##

Prepared by method L using intermediate 10353-28-1 (Reference Example41) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by dissolving the crude productresidue in aqueous methanol and treating with 2N NaOH until basic. Theproduct precipitated out of solution as a gummy semi-solid. The solventwas removed by decantation, the product was air dried and used withoutfurther purification. The deprotected product was isolated as thecarbonate salt (tan solid) in 60% yield as a tan solid, singlehomogeneous peak by HPLC (PDA detection) 15 cm C₁₈ column, eluting with55/45 H₂ O (5% NH₄ OH, 5% HOAC)/CH₃ CN; MS (Cl) 479 (MH⁺); IR (KBr)3337, 3050, 2930, 2875, 1683, 1609, 1512, 1500, 1466, 1439, 1397, 1327,1301, 1278, 1242, 1177, 1093, 750 cm⁻¹.

Compound 27 4-Benzyl-2-{2- 4-2-(N,N-bis-tert-butoxycarbonylguanidinoethyl!phenoxy!ethyl}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR48##

Prepared by Method L using intermediate 10508-23-A (Reference Compound74) and isolated as a white powder in 28% yield after columnchromatography (10% ether in hexane); IR (KBr) 3334, 2978, 1638, 1616,1330, 1132, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.51 (s, 9H),2.25-2.39 (m, 1H), 2.50-2.63 (m, 1H), 2.81 (t, J=7.2 Hz, 2H), 3.63 (q,J=7.9 Hz, 2H), 4.18-4.29 (m, 2H), 4.94 (dd, J=9.3, 3.8 Hz, 1H), 5.16 (s,2H), 6.84-7.01 (m, 6H), 7.13 (d, J=8.4 Hz, 2H), 7.23-7.34 (m, 5H), 8.38(br t, J=3.8 Hz, 1H), 11.49 (br s, 1H). Anal. Calc'd for C₃₆ H₄₄ N₄ O₇ :C, 67.06; H, 6.88; N, 8.69. Found: C, 66.80; H, 6.90; N, 8.63.

Compound 28 4-Benzyl-3,4-dihydro-2-{2- 4-2-guanidinoethyl!phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine Hydrochloride0.7 Hydrate ##STR49##

Prepared by Method K from Compound 27 and isolated as a white powder in9.1% yield; IR (KBr) 3326, 3146, 1664, 1500, 1401, 1243, 827, 751 cm⁻¹ ;Anal. Calc'd for C₂₆ H₂₈ N₄ O₃.HCl.0.7H2O: C, 63.27; H, 6.21; N, 11.35.Found: C, 63.37; H, 5.98; N, 11.06.

Compound 29 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(2-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR50##

Prepared from 2-{2- 4-2-(N,N-bis-tert-butoxycarbonylguanidino)ethyl!-phenoxy!ethyl}-3,4-dihydro-4-(2-methoxybenzyl)-3-oxo-2H-1,4-benzoxazineby methods L and K to give an off-white powder in 25% yield; IR (KBr)3164, 1663, 1501, 1405, 1245, 751 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.20-2.33 (m,1H), 2.37-2.52 (m, 1H), 2.76 (br s, 2H), 3.33 (br s, 2H), 3.87 (s, 3H),4.08-4.21 (m, 2H), 4.87 (dd, J=8.6, 4.3 Hz, 1H), 5.09 (ABq, J_(AB) =18.0Hz, 2H), 6.73-7.25 (v br s, 4H), 6.73-6.99 (m, 9H), 7.11 (d, J=7.7 Hz,2H), 7.21 (t, J=7.2 Hz, 1H), 7.67 (br s, 1H); MH⁺ at m/z=475; Anal.Calc'd for C₂₇ H₃₀ N₄ O₄.HCl.0.75H₂ O: C, 61.83; H, 6.25; N, 10.68.Found: C, 61.82; H, 6.26; N, 10.61.

Compound 30 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-(3-fluorobenzyl)-3-oxo-2H-1,4-benzoxazine##STR51##

Prepared from 10508-24-A (Reference Example 45) by Method L and isolatedas a white foam in 17% yield after chromatography using 20% EtOAc inhexane; IR (KBr) 3330, 2979, 1723, 1688, 1638, 1132, 1059, 751 cm⁻¹ ; ¹H NMR (CDCl₃) δ 1.48 (s, 9H), 1.50 (s, 9H), 2.27-2.38 (m, 1H), 2.53-2.64(m, 1H), 2.81 (t, J=7.2 Hz, 2H), 3.64 (q, J=6.8 Hz, 2H), 4.15-4.29 (m,2H), 4.94 (dd, J=9.0, 4.0 Hz, 1H), 5.15 (ABq, J_(AB) =15.2 Hz, 2H),6.81-7.04 (m, 8H), 7.13 (d, J=8.6 Hz, 2H), 7.28-7.92 (m, 2H), 8.36 (t,J=4.8 Hz, 1H), 11.47 (s, 1H); Anal. Calc'd for C₃₆ H₄₃ FN₄ O₇ : C,65.24; H, 6.54; N, 8.45. Found: C, 65.03; H, 6.43; N, 8.31.

Compound 31 3,4-Dihydro-4-(3-fluorobenzyl)-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR52##

Prepared form Compound 30 by Method K and isolated as a white foam in97% yield; IR (KBr) 3153, 1654, 1501, 753 cm⁻¹ ; ¹ H NMR (CDCl₃) δ2.18-2.33 (m, 1H), 2.37-2.52 (m, 1H), 2.78 (br s, 2H), 3.34 (v br s,2H), 4.05-4.22 (m, 2H), 4.86 (dd, J=8.7, 4.2 Hz, 1H), 5.07 (s, 2H),6.75-7.25 (br s, 4H), 6.80 (d, J=7.6 Hz, 2H), 6.84-7.00 (m, 6H), 7.12(d, J=7.7 Hz, 2H), 7.22-7.30 (m, 2H), 7.71 (br s, 1H); Anal. Calc'd forC₂₆ H₂₇ FN₄ O₃.HCl.H₂ O.0.1C₃ H₈ O: C, 60.40; H, 5.94; N, 10.71. Found:C, 60.11; H, 5.86; N, 10.42.

Compound 32 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-(3-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR53##

Prepared from intermediate 10508-22-A (Reference Example 76) by Method Land isolated as a white foam in 30% yield; IR (KBr) 3334, 2979, 1723,1686, 1645, 1615, 1329, 1246, 1156, 1132, 1059, 751 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.48 (s, 9H), 1.51 (s, 9H), 2.26-2.38 (m, 1H), 2.51-2.63 (m,1H), 2.81 (t, J=7.2 Hz, 2H), 3.64 (q, J=6.79 Hz, 2H), 3.77 (s, 3H),4.15-4.29 (m, 2H), 4.94 (dd, J=9.2, 4.0 Hz, 1H), 5.13 (s, 2H), 6.76-7.02(m, 8H), 7.12 (d, J=8.6 Hz, 2H), 7.21-7.26 (m, 2H), 8.37 (t, J=4.8 Hz,1H), 11.47 (s, 1H); Anal. Calc'd for C₃₇ H₄₆ N₄ O₈.0.1H₂ O: C, 65.68; H,6.88; N, 8.28. Found: C, 65.40;H, 6.83; N, 8.10.

Compound 33 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(3-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR54##

Prepared from Compound 32 by Method K and isolated as a CHCl₃ solublewhite foam in 21% yield; IR (neat) 3020, 1671, 1513, 1501, 1407, 1217,758 cm⁻¹ ; ¹ H NMR (CDCl₃) 2.15-2.28 (m, 1H), 2.35-2.48 (m, 1H),2.70-2.87 (m, 3H), 3.34 (br s, 2H), 3.71 (s, 3H), 4.02-4.17 (m, 2H),4.85 (dd, J=8.8, 4.0 Hz, 1H), 5.03 (ABq, J_(AB) =16.8 Hz, 2H), 6.72-7.23(m, 16H), 7.64 (br s, 1H); Anal. Calc'd for C₂₇ H₃₀ N₄ O₄.HCl.H₂ O: C,61.30; H, 6.29; N, 10.59. Found: C, 61.20; H, 6.04; N, 10.45.

Compound 34 4-(3-Benzyloxybenzyl)-2-{2- 4-2-(N,N-Bis-tert-butoxycarbonyl-guanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR55##

Prepared from 10508-82-A (Reference Example 77) by Method L and isolatedas a white foam in 35% yield after chromatography (eluting with CH₂Cl₂); IR (KBr) 3331, 2977, 1722, 1687, 1638, 1613, 1501, 1410, 1329,1245, 1156, 1131, 749 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.51 (s,9H), 2.24-2.37 (m, 1H), 2.50-2.63 (m, 1H), 2.81 (t, J=7.2 Hz, 2H), 3.63(q, J=7.1 Hz, 2H), 4.15-4.30 (m, 2H), 4.92 (dd, J=9.4, 3.9 Hz, 1H), 5.02(s, 2H), 5.12 (ABq, J_(AB) =15.4 Hz, 2H), 6.84-7.00 (m, 9H), 7.12 (d,J=8.6 Hz, 2H), 7.23-7.27 (m, 1H), 7.32-7.42 (m, 5H), 8.37 (br t, J=4.3Hz, 1H), 11.5 (s, 1H); Anal. Calc'd for C₄₃ H₅₀ N₄ O₈ : C, 68.78; H,6.71; N, 7.46. Found: C, 68.50; H, 6.78; N, 7.41.

Compound 35 4-(3-Benzyloxybenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR56##

Prepared from Compound 34 by Method K and isolated as a white foam in53% yield after repeated ether triturations, mp 100°-105° C.; IR (KBr)3338, 3155, 1676, 1610, 1513, 1500, 1400, 1243, 751 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.10-2.23 (m, 1H), 2.30-2.44 (m, 1H), 2.74 (br s, 2H), 3.32(br s, 2H), 3.97-4.15 (m, 2H), 4.81 (dd, J=8.7, 4.1 Hz, 1H), 4.96 (s,2H), 5.01 (s, 2H), 6.75-7.33 (m, 23H), 7.63 (br s, 1H); Anal. Calc'd forC₃₃ H₃₄ N₄ O₄.HCl.H₂ O: C, 65.50; H, 6.16; N, 9.26. Found: C, 65.77; H,5.98; N, 9.06.

Compound 36 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(3-hydroxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR57##

Compound 35 (0.5 g, 0.83 mmol) was reacted with H₂ at 50 psi in a Parrshaker containing containing 10% Pd/C (200 mg) in MeOH. After 2 h, thecatalyst was removed and the filtrate was concentrated in vacuum. Theproduct was isolated as a white powder in 40% yield after ethertrituration; IR (KBr) 3159, 1661, 1613, 1512, 1500, 1242, 752 cm⁻¹ ; ¹ HNMR (DMSO-d₆ plus CDCl₃) δ 2.28-2.38 (m, 1H), 2.45-2.58 (m, 1H), 2.82(t, J=7.4 Hz, 2H), 3.01 (s, HDO), 3.40 (q, J=6.8 Hz, 2H), 4.15-4.30 (m,2H), 4.91 (dd, J=9.1, 4.3 Hz, 1H), 5.08 (s, 2H), 6.69-6.75 (m, 3H),6.87-7.02 (m, 8H), 7.11-7.30 (m, 5H), 7.54 (br t, J=5.1 Hz, 1H), 9.05(s, 1H); MH⁺ at m/z=461; Anal. Calc'd for C₂₆ H₂₈ N₄ O₄.2HCl.H₂ O: C,56.63; H, 5.85; N, 10.16. Found: C, 56.46; H, 5.61; N, 9.85.

Compound 37 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(4-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR58##

Prepared by method L using intermediate 10508-19 (Reference Example 47)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K to give a white foam in 53% yield; IR (KBr) 3411, 1654, 1617,1515, 1501, 1248, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.20 (m, 1H), 2.31-2.44(m, 1H), 2.72 (br t, J=6.4 Hz, 2H), 3.29 (br t, J=6.4 Hz, 2H), 3.68 (s,3H), 3.96-4.12 (m, 2H), 4.79 (dd, J=8.8, 4.0 Hz, 1H), 4.97 (s, 2H),6.70-7.30 (v br s, 4H), 6.71-6.93 (m, 8H), 7.05-7.13 (m, 4H), 7.70 (brs, 1H); MH⁺ at m/z=475; Anal. Calc'd for C₂₇ H₃₀ N₄ O₄.HCl.H₂ O: C,61.30; H, 6.29; N, 10.59. Found: C, 61.17; H, 6.10; N, 10.25.

Compound 38 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-4-(4-phenylbenzyl)-2H-1,4-benzoxazine##STR59##

Prepared by method L using intermediate 11578-99 (Reference Example 59)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K to give a white foam in 18% overall yield; IR (KBr) 3157, 1681,1500, 1398, 1243, 759 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.20-2.33 (m, 1H),2.38-2.54 (m, 1H), 2.73-2.82 (m, 2H), 3.27-3.39 (m, 2H), 4.05-4.22 (m,2H), 4.88 (dd, J=8.9, 4.4 Hz, 1H), 5.12 (s, 2H), 6.65-7.57 (v br s, 4H),6.80 (d, J=8.4 Hz, 2H), 6.88-6.97 (m, 3H), 7.11 (d, J=8.3 Hz, 2H),7.25-7.32 (m, 4H), 7.39 (t, J=7.1 Hz, 2H), 7.51 (d, J=8.0 Hz, 4H), 7.71(br s, 1H); MH+ at m/z=521; Calc'd for C₃₂ H₃₂ N₄ O₃.HCl.H₂ O: C, 66.83;H, 6.13; N, 9.74. Found: C, 67.01; H, 5.99; N, 9.53.

Compound 39 2-{2-4-(2-Aminomethyl)phenoxy!ethyl}-4-(3,5-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR60##

Prepared by method L using intermediate 10005-181-1 (Reference Example48) and N,-t-butoxycarbonyl-(4-hydroxyphenyl)benzylamine and method K togive a white solid directly from the reaction in 73% yield, mp228.5°-230° C.; IR (KBr) 2927, 1680, 1517, 1503, 1402, 1254, 752 cm⁻¹ ;¹ H NMR (DMSO-d₆) δ 2.20-2.31 (m, 1H), 2.36-2.48 (m, 1H), 3.94 (s, 2H),4.20-4.28 (m, 2H), 5.05 (dd, J=8.5, 3.8 Hz, 1H), 5.18 (ABq, J_(AB) =16.7Hz, 2H), 6.96-7.10 (m, 6H), 7.35 (d, J=1.8 Hz, 2H), 7.43 (d, J=8.6 Hz,2H), 7.52 (t, J=1.8 Hz, 1H), 8.37 (br s, 3H); Anal. Calc'd for C₂₄ H₂₂Cl₂ N₂ O₃.HCl.0.5H₂ O: C, 57.33; H, 4.81; N, 5.57. Found: C, 57.33; H,4.77; N, 5.37.

Compound 40 4-(3,5-Dichlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR61##

Prepared by method L using intermediate 10005-181-1 (Reference Example48) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine andmethod K to give a cream-colored solid in 48% yield, mp 115.5°-117° C.;IR (KBr) 3328, 1665, 1515, 1501, 1399, 1245, 751 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 2.17-2.30 (m, 1H), 2.33-2.47 (m, 1H), 2.72 (t, J=7.2 Hz,2H), 3.28-3.48 (m, 3H), 4.15-4.24 (m, 2H), 5.02-5.06 (m, 1H), 5.18 (ABq,J_(AB) =16.7 Hz, 2H), 6.8-7.6 (v br s, 4H), 6.91 (d, J=8.5 Hz, 1H),6.99-7.10 (m, 4H), 7.20 (d, J=8.5 Hz, 2H), 7.35 (s, 2H), 7.52 (s, 1H),7.66 (t, J=5.5 Hz, 1H); Anal. Calc'd for C₂₆ H₂₆ Cl₂ N₄ O₃.HCl.0.25H₂ O:C, 56.33; H, 5.00; N, 10.11. Found: C, 56.18; H, 5.26; N, 9.90.

Compound 41 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-(3-methoxybenzyl)-3-oxo-4-(4-picolyl)-2H-1,4-benzoxazine##STR62##

Prepared by method L using intermediate 10840-22 (Reference Example 58)and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine to givean off-white powder in 20% yield; IR (KBr) 2979, 1723, 1690, 1638, 1501,1416, 1368, 1333, 1246, 1158, 751 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H),1.50 (s, 9H), 2.28-2.40 (m, 1H), 2.53-2.64 (m, 1H), 2.81 (t, J=7.2 Hz,2H), 3.63 (br q, J=7.2 Hz, 2H), 4.16-4.30 (m, 2H), 4.96 (dd, J=9.2, 4.0Hz, 1H), 5.16 (ABq, J_(AB) =14 Hz, 2H), 6.73 (dd, J=8.4, 1.5 Hz, 1H),6.85 (d, J=8.6 Hz, 2H), 6.93 (td, J=7.2, 2.0 Hz, 1H), 6.97-7.06 (m, 2H),7.12-7.17 (m, 4H), 8.36 (br t, J=4.8 Hz, 1H), 8.56 (dd, J=4.5, 1.6 Hz,2H), 11.47 (s, 1H); Anal. Calc'd for C₃₅ H₄₃ N₅ O₇ : C, 65.10; H, 6.71;N, 10.85. Found: C, 64.73; H, 6.69; N, 10.46.

Compound 42 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-4-(4-picolyl)-2H-1,4-benzoxazine##STR63##

Prepared from Compound 41 by Method K and isolated as a white solid in30% yield after trituration with ether, mp 244°-248° C.; IR (KBr) 3184,1673, 1640, 1499, 1403, 1248, 760 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 2.20-2.35(m, 1H), 2.35-2.48 (m, 1H), 2.72 (t, J=7.2 Hz, 2H), 3.32 (q, J=66 Hz,2H), 3.50-4.50 (v br s, 1H), 4.15-4.26 (m, 2H), 5.07 (dd, J=8.8, 4.1 Hz,1H), 5.40 (ABq, J_(AB) =18.1 Hz, 2H), 6.80-7.55 (v br s, 4H), 6.87-7.13(m, 6H), 7.21 (d, J=8.6 Hz, 2H), 7.66 (t, J=5.6 Hz, 1H), 7.78 (d, J=6.3Hz, 2H), 8.78 (d, J=6.4 Hz, 2H); MH+ at m/z=446; Anal. Calc'd for C₂₅H₂₇ N₅ O₃.2HCl.0.5H₂ O: C, 56.93; H, 5.73; N, 13.28. Found: C, 56.87; H,5.60; N, 13.06.

Compound 43 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(1-naphthylmethyl)-3-oxo-2H-1,4-benzoxazine##STR64##

Prepared by method L using intermediate 10508-84-A1 (Reference Example78) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethylguanidine andmethod K using trifluoroacetic acid with anisole present, instead ofIPA/HCl. The crude material was treated with CH₂ Cl₂ /ether to give thetitle compound as a cream-colored solid in 72% yield; m.p. 75°-80° C.;IR (KBr) 3360, 1671, 1501, 1405, 1204, 1136, 799, 723 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 2.29-2.37 (m, 1H), 2.37-2.50 (m, 1H), 2.72 (t, J=7.4 Hz,2H), 3.28-3.48 (m, 2H), 3.31-3.39 (m, 2H), 3.48 (v br s, 1H), 4.16-4.29(m, 2H), 5.08 (dd, J=8.8, 4.2 Hz, 1H), 5.62 (ABq, J_(AB) =17.4 Hz, 2H),6.86-7.66 (v br s, 4H), 6.86-7.06 (m, 4H), 7.11 (d, J=8.1 Hz, 2H), 7.20(d, J=8.6 Hz, 2H), 7.40 (t, J=7.7 Hz, 1H), 7.48-7.55 (m, 1H), 7.58-7.68(m, 2H), 7.85 (d, J=8.2 Hz, 1H), 8.00 (d, J=9.1 Hz), 8.21 (d, J=8.1 Hz);MH⁺ at m/z=495; Anal. Calc'd for C₃₀ H₃₀ N₄ O₃.C₂ HF₃ O₂ :C, 62.38; H,5.06; N, 9.04. Found: C, 62.38; H, 5.06; N, 9.04.

Compound 44 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-(2-naphthylmethyl)-3-oxo-2H-1,4-benzoxazine##STR65##

Prepared by method L using intermediate 10508-80-1 (Reference Example79) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine. Thecrude material was purified by flash chromatography eluting withEtOAc/hexane to afford the product as a white foam in 24% yield; IR(KBr) 3330, 3053, 2977, 2931, 1722, 1638, 1614, 1512, 1501, 1366, 1330,1244, 1156, 1131, 748 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.51 (s,9H), 2.31-2.44 (m, 1H), 2.55-2.68 (m, 1H), 2.82 (t, J=7.1 Hz, 2H), 3.65(q, J=6 Hz, 2H), 4.20-4.33 (m, 2H), 5.00 (dd, J=9.4, 3.4 Hz, 1H), 5.32(ABq, J_(AB) =15.4 Hz, 2H), 6.84-6.96 (m, 5H), 7.00 (t, J=6.8 Hz, 1H),7.14 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.45-7.48 (m, 2H), 7.68(s, 1H), 7.75-7.83 (m, 3H), 8.20 (br s, 1H), 11.48 (s, 1H); Anal. Calc'dfor C₄₀ H₄₆ N₄ O₇ : C, 69.14; H, 6.67; N, 8.06. Found: C, 69.16; H,6.88; N, 7.63.

Compound 45 3,4-Dihydro-2-{2-4-(2-guanidinylethyl)phenoxy!ethyl}-4-(2-naphthylmethyl)-3-oxo-2H-1,4-benzoxazine##STR66##

Prepared from Compound 44 by Method K and triturated with ether toafford the title compound as a white solid in 80% yield, mp 173°-178°C.; IR (KBr) 3154, 1680, 1501, 1400, 1241, 752 cm⁻¹ ; ¹ H NMR (DMSO-d₆)2.22-2.35 (m, 1H), 2.38-2.48 (m, 1H), 2.72 (t, J=7.3 Hz, 2H), 3.28-3.38(m, 2H), 4.17-4.26 (m, 2H), 5.05 (dd, J=8.7, 4.0 Hz, 1H), 5.34 (ABq,J_(AB) =16.2 Hz, 2H), 6.80-7.80 (v br s, 4H), 6.92-7.01 (m, 4H), 7.08(t, J=7.3 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H),7.48-7.51 (m, 2H), 7.59 (br t, J=5.1 Hz, 1H), 7.78 (s, 1H), 7.83-7.91(m, 3H); MH⁺ at m/z=495; Anal. Calc'd for C₃₀ H₃₀ N₄ O₃.HCl.0.7H₂ O: C,66.28; H, 6.01; N, 10.31. Found: C, 66.30; H, 5.88; N, 10.06.

Compound 46 3,4-Dihydro-2-{2-4-(2-guanidinylethyl)phenoxy!ethyl}-3-oxo-2H-4-(3-thienylmethyl)-1,4-benzoxazine##STR67##

Prepared by method L using intermediate 11721-108-1 (ReferenceIntermediate 85) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine and method K using trifluoroacetic acid with anisole present,instead of IPA/HCl. The crude product was purified by flashchromatography using 1% MeOH in CH₂ Cl₂ to 6% MeOH/1% NH₄ OH in CH₂ Cl₂,and isolated in 48% yield as a tan foam, mp 66°-71° C.; IR (KBr) 3364,1655, 1500, 1246, 1203, 1136, 751 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 2.11-2.26(m, 1H), 2.3-2.43 (m, 1H), 2.73 (t, J=6.9 Hz, 2H), 3.28-3.39 (m, 1H),4.13-4.22 (m, 2H), 4.93 (dd, J=8.8, 4.1 Hz, 1H), 5.12 (ABq, J_(AB) =17.2Hz, 2H), 6.91 (d, J=8.6 Hz, 3H), 6.99-7.04 (m, 5H), 7.12-7.22 (m, 2H),7.19 (d, J=8.6 Hz, 2H), 7.40 (d, J=2.3 Hz, 1H), 7.52 (dd, J=4.6, 2.3 Hz,1H), 7.62 (t, J=5.75 Hz, 1H); MH⁺ at m/z=451; Anal. Calc'd for C₂₄ H₂₆N₄ O₃ S.C₂ HF₃ O₂ : C, 51.61; H, 4.39; N, 8.85. Found: C, 51.34; H,4.60; N, 8.85.

Compound 47 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(2-chloro-4-thienylmethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR68##

Prepared from 10508-79 (Reference Example 80) by method L using equalequivalents of reagents to starting material and isolated as a whitefoam in 24% yield; IR (KBr) 3330, 2978, 1722, 1686, 1638, 1615, 1500,1413, 1331, 1247, 1130, 1058, 748 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H),1.51 (s, 9H), 2.20-2.32 (m, 1H), 2.81 (t, J=7.2 Hz, 2H), 3.60-3.66 (m,2H), 4.12-4.28 (m, 2H), 4.78 (dd, J=9.3,4.0 Hz, 1H), 5.16 (ABq, J_(AB)=15.8 Hz, 2H), 6.75 (d, J=3.8 Hz, 1H), 6.82-6.85 (m, 3H), 7.00-7.08 (m,4H), 7.12 (d, J=8.6 Hz, 2H), 8.37 (t, J=3.5 Hz, 1H), 11.47 (s, 1H);Anal. Calc'd for C₃₄ H₄₁ ClN₄ O₇ S: C, 59.60; H, 6.03; N, 8.18. Found:C, 59.27; H, 6.02; N, 8.01.

Compound 48 4-(2-Chloro-4-thienylmethyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-² H-1,4-benzoxazine ##STR69##

Prepared from Compound 47 by method K in 88% crude yield. This crudematerial was leached with EtOAc to remove the impurities to afford theproduct as a white foam; IR (KBr) 3148, 1667, 1500, 1450, 1399, 1243,1058, 749 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.04-2.23 (m, 3H), 2.30-2.41 (m, 1H),2.72-2.83 (m, 2H), 3.28-3.40 (m, 2H), 3.97-4.15 (m, 2H, ), 4.77 (dd,J=7.7, 3.4 Hz, 1H), 5.06 (ABq, J_(AB) =14.5 Hz, 2H), 6.69-7.20 (v br s,4H), 6.69-6.80 (m, 3H), 6.92-7.06 (m, 5H), 7.11 (d, J=8.1 Hz, 2H), 7.64(br s, 1H); Anal. Calc'd for C₂₄ H₂₅ ClN₄ O₃ S.HCl.H₂ O: C, 53.43; H,5.23; N, 10.39. Found: C, 53.08; H, 5.27; N, 10.32.

Compound 49 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-6-chloro-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR70##

Prepared from 11578-71 (Reference Example 49) by Method L using equalequivalents of reagents to starting material and isolated in 34% yieldas a colorless oil after chromatography (eluting with CH₂ Cl₂); IR(neat) 3332, 2978, 1721, 1694, 1638, 1615, 1498, 1415, 1367, 1132, 811,777 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.51 (s, 9H), 2.25-2.37 (m,1H), 2.54-2.66 (m, 1H), 2.82 (t, J=7.2 Hz, 2H), 3.63 (q, J=5.6 Hz, 2H),4.16-4.25 (m, 2H), 4.94 (dd, J=9.3, 3.9 Hz, 1H), 5.09 (ABq, J_(AB) =16.1Hz, 2H), 6.80 (s, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.95 (s, 2H), 7.13 (d,J=8.5 Hz, 3H), 7.23-7.31 (m, 3H), 8.37 (br t, J=2 Hz, 1H), 11.47 (s,1H); Anal. Calc'd for C₃₆ H₄₂ Cl₂ N₄ O₇ : C, 60.59; H, 5.93; N, 7.85.Found: C, 60.65; H, 6.04; N, 7.65.

Compound 50 6-Chloro-4-(3-chlorobenzyl)-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR71##

Prepared from Compound 49 by Method K where the product was isolated asa white foam from CH₂ Cl₂ in 28% yield; IR (KBr) 3154, 1684, 1668, 1496,1376, 1264, 1243, 1092 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.13-2.27 (m, 1H),2.35-2.50 (m, 1H), 2.74 (br s, 2H), 3.31 (br s, 2H), 4.00-4.14 (m, 2H),4.84 (dd, J=9.0, 4.2 Hz, 1H), 4.98 (ABq, J_(AB) =17.5 Hz, 2H), 6.73-7.29(m, 15H), 7.61 (br s, 1H); MH⁺ at m/z=513; Anal. Calc'd for C₂₆ H₂₆ Cl₂N₄ O₃.HCl.0.7H₂ O.0.2C₃ H₈ O: C, 55.61; H, 5.26; N, 9.75. Found; C,55.83; H, 5.01; N, 9.51.

Compound 51 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-6-phenyl-2H-1,4-benzoxazine##STR72##

Prepared from 11578-41 (Reference Example 44) by Method L and isolatedas an oil in 46% yield. This material was crystallized from ether/hexaneto afford a white crystalline solid, mp 115°-116° C.; IR (KBr) 2976,2931, 1724, 1689, 1642, 1614, 1430, 1336, 1135, 766 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.48 (s, 9H), 1.50 (s, 9H), 2.30-2.43 (m, 1H), 2.35-2.46 (m,1H), 2.81 (t, J=7.3 Hz, 2H), 3.63 (q, J=7.1 Hz, 2H), 4.17-4.32 (m, 2H),4.99 (dd, J=9.3, 3.9 Hz, 1H), 5.18 (ABq, J_(AB) =25.7 Hz, 2H), 6.87 (d,J=8.5 Hz, 2H), 7.04-7.40 (m, 14H), 8.38 (t, J=4.3 Hz, 1H), 11.47 (br s,1H); Anal. Calc'd for C₄₂ H₄₇ ClN₄ O₇ : C, 66.79; H, 6.27; N, 7.42.Found: C, 66.49; H, 6.20; N, 7.34.

Compound 52 4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-6-phenyl-2H-1,4-benzoxazine##STR73##

Prepared from Compound 51 by Method K and isolated as a yellow powder in20% yield; IR (KBr) 3149, 1666, 1609, 1512, 1241, 1076, 1051, 761 cm⁻¹ ;¹ H NMR (CD₃ OD) δ 2.31-2.40 (m, 1H), 2.43-2.54 (m, 1H), 2.81 (t, J=7.2Hz, 2H), 3.41 (t, J=7.0 Hz, 2H), 4.20-4.31 (m, 2H), 4.85 (s, 5H plus CD₃OH), 4.99 (dd, J=11.1, 4.5 Hz, 1H), 5.28 (s, 2H), 6.91 (d, J=8.6 Hz,2H), 7.08 (d, J=8.3 Hz, 1H), 7.12-7.43 (m, 13H); Anal. Calc'd for C₃₂H₃₁ ClN₄ O₃.HCl.1.4H₂ O: C, 62.32; H, 5.69; N, 9.08. Found: C, 61.95; H,5.51; N, 9.27.

Compound 53 2-{2- 4-2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-6-trifluoromethyl-2H-1,4-benzoxazine##STR74##

Prepared from 11578-56 (Reference Example 50) by method L using equalequivalents of reagents and isolated as a colorless oil in 18% yieldafter SiO₂ column chromatography (CH₂ Cl₂); IR (KBr) 3333, 2979, 1723,1696, 1639, 1617, 1453, 1330, 1303, 1165, 1129, 824 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.48 (s, 9H), 1.51 (s, 9H), 2.26-2.40 (m, 1H), 2.55-2.67 (m,1H), 2.82 (t, J=7.1 Hz, 2H), 3.63 (q, J=5.4 Hz, 2H), 4.06-4.27 (m, 2H),5.02 (dd, J=9.2, 3.9 Hz, 1H), 5.14 (ABq, J_(AB) =16.1 Hz, 2H), 6.84 (d,J=8.5 Hz, 2H), 7.05-7.17 (m, 3H), 7.13 (d, J=8.5 Hz, 2H), 7.23-7.30 (m,4H), 8.37 (br t, J=4.3 Hz, 1H), 11.48 (s, 1H); Anal. Calc'd for C₃₇ H₄₂ClF₃ N₄ O₃ : C, 59.48; H, 5.67; N, 7.50. Found: C, 59.60; H, 5.67; N,7.39.

Compound 54 4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!-ethyl}-3-oxo-6-trifluoromethyl-2H-1,4-benzoxazine##STR75##

Prepared from Compound 53 by Method K and isolated as a white foam in27% yield; IR (KBr) 3336, 3159, 1667, 1453, 1304, 827 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.20-2.39 (m, 1H), 2.48 (br s, 3H), 2.77 (br s, 2H), 3.35 (brs, 2H), 4.08 (br s, 2H), 4.93 (dd, J=8.6, 4.0 Hz, 1H), 5.06 (ABq, J_(AB)=16.8 Hz, 2H), 6.75-7.30 (v br s, 4H), 6.77 (d, J=7.7 Hz, 2H), 7.01-7.26(m, 7H), 7.25 (d, J=7.1 Hz, 2H), 7.64 (v br s, 1H); MH⁺ at m/z=547;Anal. Calc'd for C₂₇ H₂₆ ClF₃ N₄ O₃.HCl.0.7H₂ O: C, 54.41; H, 4.80; N,9.40. Found: C, 54.49; H, 4.74; N, 9.32.

Compound 55 4-(3-Chlorobenzyl)-3,4-dihydro-7-fluoro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR76##

Prepared from 11578-47 (Reference Example 52) andN,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine by Method Lusing equal equivalents of reagents and by Method K. The product wasisolated in 17% overall yield as a white foam; IR (KBr) 2877, 1664,1509, 1405, 1243, 1154, 852 cm⁻¹ ; ¹ H NMR (CD₃ OD) 2.26-2.37 (m, 1H),2.42-2.53 (m, 1H), 2.83 (t, J=6.8 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H),4.17-4.29 (m, 2H), 4.84 (s, 6.4H plus CD₃ OH), δ 4.98 (dd, J=8.4, 4.4Hz, 1H), 5.18 (s, 2H), 6.73 (td, J=8.8, 2.6 Hz, 1H), 6.83 (dd, J=9.2,2.8 Hz, 1H), 6.92 (d, J=8.0 Hz, 2H), 6.97 (dd, J=8.8, 5.2 Hz, 1H), 7.17(d, J=8 Hz, 2H), 7.17-7.22 (m, 1H), 7.25-7.35 (m, 3H); MH⁺ at m/z=497;Anal. Calc'd for C₂₆ H₂₆ ClFN₄ O₃.HCl.0.7H₂ O: C, 57.19; H, 5.24; N,10.26. Found: C, 56.81; H, 5.36; N, 10.26.

Compound 56 2-{2- 4-2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR77##

Prepared from 11578-33 (Reference Example 56) andN,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine by Method Lusing equal equivalents of reagents to starting material and isolated aswhite solid in 27% yield after SiO₂ column chromatography eluting withCH₂ Cl₂, mp 115°-117° C.; IR (KBr) 2977, 1699, 1639, 1615, 1593, 1367,1131, 1058, 810, 776 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.51 (s.9H), 2.25-2.37 (m, 1H), 2.52-2.67 (m, 1H), 2.82 (t, J=7.2 Hz, 2H), 3.63(q, J=7.1 Hz, 2H), 4.13-4.24 (m, 1H), 4.27-4.35 (m, 1H), 5.05 (dd,J=9.7, 3.5 Hz, 1H), 5.10 (s, 2H), 6.71 (d, J=2.2 Hz, 1H), 6.86 (d, J=8.6Hz, 2H), 7.05 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 7.13 (s, 1H),7.26-7.29 (m, 3H), 8.37 (t, J=2.6 Hz, 1H), 11.48 (s, 1H); Anal. Calc'dfor C₃₆ H₄₁ Cl₃ N₄ O₇ : C, 57.80; H, 5.52; N, 7.49. Found: C, 57.64; H,5.39; N, 7.77.

Compound 57 4-(3-Chlorobenzyl)-6,8-dichloro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR78##

Prepared from Compound 56 by method K and isolated as a white foam in75% yield; IR (KBr) 3150, 1666, 1591, 1479, 1242, 743 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 2.23-2.37 (m, 1H), 2.50-2.61 (m, 1H), 2.84 (t, J=7.1 Hz,2H), 3.39 (q, J=5.9 Hz, 2H), 4.15-4.23 (m, 1H), 4.25-4.35 (m, 1H), 5.04(dd, J=9.8, 3.8 Hz, 1H), 5.11 (ABq, J_(AB) =16.3 Hz, 2H), 6.75 (d, J=2.2Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 7.07-7.21 (m, 9H), 7.26-7.35 (m, 2H),7.67 (br t, J=5.1 Hz, 1H); MH⁺ at m/z=547; Anal. Calc'd for C₂₆ H₂₅ Cl₃N₄ O₃.HCl.0.7H₂ O: C, 52.31; H, 4.63; N, 9.39. Found: C, 52.37; H, 4.59;N, 9.37.

Compound 58 4-(3-Chlorobenzyl)-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3,4-dihydro-7-methyl-3-oxo-2H-1,4-benzoxazine ##STR79##

Prepared by method L using intermediate 11578-52 (Referenced Example 55)and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine and methodK in 2.5% overall yield as a white foam; IR (KBr) 3340, 3161, 1668,1402, 1244, 1178, 1146, 1107, 1056 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.15-2.28(m, 1H), 2.20 (s, 3H), 2.34-2.47 (m, 3H), 2.76 (t, J=6.4 Hz, 2H),3.30-3.40 (m, 2H), 4.00-4.18 (m, 2H), 4.83 (dd, J=8.9, 4.3 Hz, 1H), 5.01(s, 2H), 6.63-7.27 (v br s, 4H), 6.63-6.70 (m, 2H), 6.75-6.83 (m, 2H),7.03-7.23 (m, 7H), 7.63 (br s, 1H); MH+ at m/z=493; Anal. Calc'd for C₂₇H₂₉ ClN₄ O₃.HCl.H₂ O: C, 59.23; H, 5.89; N, 10.23. Found: C, 58.84; H,5.60; N, 10.07.

Compound 59 2-{2- 4-2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine##STR80##

Prepared from 10840-117-1 (Reference Example 88) by Method L andisolated as a white foam in 13% yield; IR (KBr) 3334, 2978, 2933, 1722,1686, 1639, 1614, 1513, 1504, 1417, 1131, 750 cm⁻¹ ; ¹ H NMR (CDCl₃) δ1.48 (s, 9H), 1.50 (s, 9H), 2.19-2.31 (m, 1H), 2.45-2.56 (m, 1H), 2.81(t, J=7.2 Hz, 2H), 3.38 (s, 3H), 3.63 (q, J=5.3 Hz, 2H), 4.10-4.26 (m,2H), 4.83 (dd, J=8.8, 4.0 Hz, 1H), 6.84 (d, J=6.84 Hz, 2H), 6.95-7.07(m, 4H), 7.12 (d, J=8.6 Hz, 2H), 8.36 (br t, J=4.0 Hz, 1H), 11.47 (s,1H); Anal. Calc'd for C₃₀ H₄₀ N₄ O₇.0.2H₂ O: C, 62.96; H, 7.12; N, 9.79.Found: C, 62.88; H, 7.20; N, 9.71.

Compound 60 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-methyl-3-oxo-2H-1,4-benzoxazine##STR81##

Prepared by dissolving Compound 59 in CH₂ Cl₂ and treating with TFA.Solvent removal and purification by SiO₂ chromatography (2-6% MeOH inCH₂ Cl₂) followed by crystallization from MeOH/CH₂ Cl₂ /ether affordedan 82% yield of a cream colored solid, mp 80° (shrinks) 82°-85° C.; IR(KBr) 3339, 3176, 1682, 1515, 1505, 1383, 1249, 1137, 755 cm⁻¹ ; ¹ H NMR(DMSO-d₆) δ 2.08-2.16 (m, 1H), 2.27-2.33 (m, 1H), 2.71 (t, J=7.5 Hz,2H), 3.27-3.35 (m, 2H), 3.30 (s, 3H), 4.10-4.18 (m, 2H), 4.81 (dd,J=8.8, 4.2 Hz, 1H), 6.83-7.50 (v br s, 4H), 6.90 (d, J=8.6 Hz, 2H),7.00-7.12 (m, 4H), 7.18 (d, J=8.7 Hz, 2H), 7.56 (br t, J=5.7 Hz, 1H);MH⁺ at m/z=369.

Compound 61 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-4-pentyl-2H-1,4-benzoxazine##STR82##

Prepared from intermediate 10840-185 (Reference Example 60) by Method Kand isolated as a colorless glass in 98% yield; IR (KBr) 3154, 1661,1513, 1500, 1244, 751 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.88 (t, J=6.5 Hz, 3H),1.19 (d, isopropanol), 1.25-1.37 (m, 4H), 1.52-1.68 (m, 2H), 2.09-2.21(m, 1H), 2.30-2.40 (m, 1H), 2.79 (br s, 2H), 3.38 (br s, 2H), 3.84 (t,J=6.7 Hz, 2H), 4.00-4.15 (m, 2H plus isopropanol), 4.71 (dd, J=8.7, 4.0Hz, 1H), 6.70-7.17 (v br s, 4H), 6.78 (d, J=7.5 Hz, 2H), 6.93-7.07 (m,4H), 7.13 (d, J=7.4, 2H), 7.67 (br d, 1H); MH⁺ at m/z=425; Anal. Calc'dfor C₂₄ H₃₂ N₄ O₃.HCl.0.1C₃ H₈ O.0.6H₂ O: C, 61.00; H, 7.38; N, 11.73.Found: C, 61.04; H, 7.27; N, 11.67.

Compound 62 4-(3-Chlorobenzyl)-3,4-dihydro-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3-oxo-2H-pyrido 4,3-b!-1,4-oxazine##STR83##

Prepared by method L using intermediate 11578-190 (Reference Example 84)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine andmethod K in 35% as an off-white foam; IR (KBr) 3134, 1701, 1669, 1642,1508, 1240, 1178, 1161, 1055, 824 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 2.50 (m, 1Hplus DMSO-d₅), 2.71 (t, J=7.5 Hz, 2H), 3.28-3.35 (m, 3H), 4.17 (t, J=5.6Hz, 2H), 5.25 (ABq, J_(AB) =16.5 Hz, 2H), 5.52 (t, J=6.9, 1H), 6.70-7.60(v br s, 5H), 6.83 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.28-7.40(m, 3H), 7.48 (s, 1H), 7.50 (s, 1H), 7.67 (t, J=5.4 Hz, 1H), 8.39 (s,1H), 8.40 (s, 1H); MH⁺ at m/z=480; Anal. Calc'd for C₂₅ H₂₆ ClN₅O₃.2HCl.1.5H₂ O: C, 51.78; H, 5.39; N, 12.08. Found: C, 51.78; H, 5.39;N, 12.08.

Compound 63 2-{2- 3-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(3,5-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR84##

Prepared from 10005-181-1 (Reference Example 48) by Method L andisolated in 84% yield as a white solid after flash chromatographyeluting with 2.5-10% EtOAc in CH₂ Cl₂ and crystallization from CH₂ Cl₂/ether/hexane, mp 116°-118° C.; IR (KBr) 3359, 1688, 1505, 1256, 1171,752 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.44 (s, 9H), 2.28-2.39 (m, 1H), 2.52-2.62(m, 1H), 2.77 (t, J=9 Hz, 2H), 3.33-3.41 (m, 2H), 4.16-4.30 (m, 2H),4.54 (br s, 1H), 4.94 (dd, J=10.5, 3 Hz, 1H), 5.09 (ABq, J_(AB) =18 Hz,2H), 6.75-6.83 (m, 4H), 6.93-7.06 (m, 3H), 7.13 (d, J=1.8 Hz, 2H),7.20-7.27 (m, 2H); Anal. Calc'd for C₃₀ H₃₂ Cl₂ N₂ O₅ : C, 63.05; H,5.64; N, 4.90. Found: C, 63.24; H, 5.60; N, 4.71.

Compound 64 2-{2-3-(2-Aminoethyl)phenoxy!ethyl}-4-(3,5-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR85##

Prepared by methods J using intermediate 10005-181-1 (Reference Example48) and 4- 2-(N-t-butoxycarbonylamino)ethyl!phenol as well as method Kto give a white solid, 58% yield. mp 173.5°-176° C.; IR (KBr) 2942,1684, 1592, 1501, 1399, 1265, 752 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 2.19-2.32(m, 1H), 2.35-2.47 (m, 1H), 3.84-3.89 (m, 2H), 3.01-3.06 (m, 2H),4.19-4.24 (m, 2H), 5.03-5.08 (m, 1H), 5.18 (ABq, J_(AB) =16.7 Hz, 2H),6.83-6.87 (m, 3H), 6.99-7.09 (m, 4H), 7.25 (t, J=7.6 Hz, 1H), 7.35 (d,J=1.8 Hz, 2H), 7.52 (t, J=1.8 Hz, 1H), 8.06 (br s, 3H); Anal. Calc'd forC₂₅ H₂₄ Cl₂ N₂ O₃.HCl.0.25 H₂ O: C, 58.61; H, 5.02; N, 5.47. Found: C,58.47; H, 4.88; N, 5.33.

Compound 65 2-{2- 4-2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4-(4-methylbenzyl)-2H-1,4-benzoxazine##STR86##

Intermediate 10840-45 (1 eq, Reference Example 92) was dissolved in 7 mLCH₂ Cl₂ /ether (3/1) under nitrogen and treated with triethylamine (1.2eq) followed by methanesulfonyl chloride (1.2 eq). The mixture wasstirred for 0.5 h and filtered. The filtrate was concentrated undervacuum and the residue was redissolved in ether and washed with H₂ O anddried over MgSO₄. Ether removal produced the desired methanesulfonateproduct. This crude material (1 eq) was dissolved in DMSO (1.7 mL) andtreated with the corresponding phenol (1 eq) plus NaOH pellets (3 eq).This solution was stirred at 50° C. for 24 h under nitrogen and thendiluted with H₂ O. A CH₂ Cl₂ /EtOAc solution of the precipitate waswashed with H₂ O and dried over MgSO₄. Solvent removal produced thecrude material which was purified by flash chromatography to afford theproduct in 16% overall yield and isolated as a white powder; IR (KBr)2979, 1723, 1650, 1625, 1513, 1246, 1156, 1133, 743 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.47 (s, 9H), 1.50 (s, 9H), 2.03-2.17 (m, 2H), 2.33 (s, 3H),2.81 (t, J=7.2 Hz, 2H), 3.18 (dd, J=11.9 7.2 Hz, 1H), 3.34 (dd, J=11.9,2.5, 1H), 3.63 (q, J=6.8 Hz, 2H), 4.08-4.23 (m, 2H), 4.38-4.45 (m, 3H),6.62 (dt, J=7.5, 1.5 Hz, 1H), 6.69 (dd, J=7.5, 1.5 Hz, 1H), 6.75-6.84(m, 2H), 6.82 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H, 7.16 (br q,J_(AB) =8.1 Hz, 4H), 8.36 (br t, J=4.8 Hz, 1H), 11.46 (s, 1H); Anal.Calc'd for C₃₇ H₄₈ N₄ O₆ : C, 68.92; H, 7.50; N, 8.69. Found: C, 68.65;H, 7.24; N, 8.56.

Compound 66 3,4-Dihydro-2-{2- 4-2-guanidinoethyl!phenoxy!ethyl}-4-(4-methylbenzyl)-2H-1,4-benzoxazine##STR87##

Prepared from Compound 65 by Method K in 3% yield and isolated as agreen powder after trituration with CHCl₃ ; IR (KBr) 3157, 1663, 1611,1513, 1300, 1241, 743 cm⁻¹ ; ¹ H NMR (CD₃ OD) δ 2.04-2.14 (m, 2H), 2.30(s, 3H), 2.81 (t, J=7.2 Hz, 2H), 3.18 (dd, J=12.0, 8.0 Hz, 1H),3.36-3.49 (m, 3H), 4.07-4.2 (m, 2H), 4.37-4.46 (m, 1H), 4.50 (s, 2H),6.70-6.95 (m, 7H), 7.05-7.40 (m, 9H); Anal. Calc'd for C₂₇ H₃₂ N₄O₂.HCl.1.75H₂ O: C, 63.37; H, 7.31; N, 11.26. Found: C, 63.40; H, 7.14;N, 11.21.

Compound 67 2-{2- 4-2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(2,4-dichlorobenzyl)-3,4-dihydro-2H-1,4-benzoxazine##STR88##

Prepared from 10840-8 (Reference Example 94) by Method L in 20% yieldand isolated as a white foam; IR (KBr) 3336, 2979, 2932, 1723, 1640,1617, 1366, 1133 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 1.50 (s, 9H),2.08-2.20 (m, 2H), 2.81 (t, J=7.2 Hz, 2H), 3.31 (dd, J=11.7, 7.5 Hz,1H), 3.41 (dd, J=11.6, 2.6 Hz, 1H), 3.64 (q, J=6.5 Hz, 2H), 4.10-4.27(m, 2H), 4.44-4.53 (m, 1H), 4.46 (s, 2H), 6.45 (dd, J=8.0, 1.3 Hz, 1H),6.65 (td, J=7.6, 1.4 Hz, 1H), 6.76 (td, J=7.8, 1.6 Hz, 1H), 6.80-6.87(m, 3H), 7.10-7.24 (m, 4H), 7.42 (d, J=1.9 Hz, 1H), 8.35 (t, J=4.1 Hz,1H), 11.46 (s, 1H); Anal. Calc'd for C₃₆ H₄₄ Cl₂ N₄ O₆.0.5H₂ O: C,61.01; H, 6.40; N, 7.91. Found: C, 61.14; H, 6.37; N, 7.83.

Compound 68 (2,4-Dichlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-2H-1,4-benzoxazine ##STR89##

Prepared from Compound 67 by Method K in 4.5% yield and isolated as agreen glass; IR (neat) 3334, 3166, 1665, 1611, 1513, 1246, 1219, 1046,830 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.74 (br s, 2H), 1.94-2.15 (m, 2H), 2.80(br t, J=5.6 Hz, 2H), 3.20-3.38 (m, 4H), 4.02-4.18 (m, 2H), 4.32-4.47(m, 1H), 4.42 (s, 2H), 6.35-7.40 (v br s, 4H), 6.41 (dd, J=8.0, 1.1 Hz,1H), 6.61 (td, J=7.6, 1.2 Hz, 1H), 6.73 (td, J=7.9, 1.5 Hz, 1H), 6.80(d, J=7:9 Hz, 2H), 7.10-7.20 (m, 5H), 7.39 (d, J=1.8 Hz, 1H), 7.80 (brs, 1H); MH⁺ at m/z=499; Anal. Calc'd for C₂₆ H₂₈ Cl₂ N₄ O₂.HCl.H₂ O: C,56.38; H, 5.64; N, 10.11. Found: C, 56.68; H, 5.41; N, 9.97.

Compound 69 2-{2-3-(2-(t-Butoxycarbonylamino)ethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR90##

Prepared from 10488-22 (Reference Example 66) and 3-2-(N-t-butoxycarbonylamino)ethyl!phenol by method J. The product wasisolated in 82% yield after chromatography, to afford an oil whichcrystallized on standing, mp 107°-108° C.; MS (Cl) MH⁺ no peak found; IR(KBr) 3319, 2986, 1597, 1532, 1505, 1468, 1445, 1402, 1368, 1323, 1271,1171, 1061, 787, 752 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.23 (m, 5H), 7.13 (m,1H), 7.00 (m, 2H), 6.94 (m, 1H), 6.78 (m, 3H), 5.18 (d, 1H, J=16.0 Hz),5.08 (d, 1H, J=16.0 Hz), 4.9 (dd, 1H, J=3.9, 9.2 Hz), 4.55 (br. s., 1H),4.24 (m, 2H), 3.38 (m, 2H), 2.76 (t, 2H, J=6.9 Hz), 2.58 (m, 1H), 2.34(m, 1H), 1.43 (s, 9H). Anal. Calc'd for C₃₀ H₃₃ ClN₂ O₅.0.4H₂ O: C66.21, H 6.26, N 5.15. Found: C 66.28, H 6.13, N 5.02.

Compound 70 2-{2-3-(2-Aminoethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR91##

Prepared from Compound 69 by method K in quantitative yield, mp: 163° C.darkens, 169°-171° C. melts; MS (Cl) MH⁺ 437; IR (KBr) 2948, 1678, 1599,1503, 1468, 1447, 1402, 1321, 1265, 1171, 1115, 1051, 939, 866 cm⁻¹ ; ¹H NMR (DMSO-d₆) δ 8.80-8.00 (v br s, 2H), 7.22 (m, 4H), 7.10 (m, 1H),6.95 (m, 3H), 6.80 (m, 4H), 5.13 (d, 1H, J=16.3 Hz), 5.05 (d, 1H, J=16.3Hz), 4.89 (dd, 1H, J=3.8, 8.8 Hz), 4.19 (m, 2H), 3.28 (br s, 2H), 3.08(br s, 2H), 2.49 (m, 1H), 2.27 (m, 1H), 2.52-1.50 (v br s, 1H). Anal.Calc'd for C₂₅ H₂₅ Cl N₂ O₃.HCl: C 63.43, H 5.54, N 5.92. Found: C63.16, H 5.40, N 5.73.

Compound 71 2-{2- 4-2-(N,N-'Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR92##

Prepared from 10488-22 (Reference Example 66) andN,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine by method Jin 31% yield, mp: 74°-78° C.; MS (FAB) MH⁺ 679; IR (KBr) 3332, 2979,1723, 1688, 1501, 1414, 1368, 1329, 1246, 1132, 1059, 750 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 11.47 (br s, 1H), 8.36 (br t, 1H), 7.25 (s, 2H), 7.14 (d, 2H,J=3.7 Hz), 7.06 (m, 2H), 6.92 (m, 4H), 6.84 (m, 2H), 5.19 (d, 1H, J=16.0Hz), 5.08 (d, 1H, J=16.0 Hz), 4.94 (dd, 1H, J=3.9, 9.3 Hz), 4.22 (m,2H), 3.63 (m, 2H), 2.81 (t, 2H, J=7.2 Hz), 2.58 (m, 1H), 2.34 (m, 1H),1.50 (s, 9H), 1.48 (s, 9H). Anal. Calc'd for C₃₆ H₄₃ ClN₄ O₇.0.4 H₂ O: C62.99, H 6.43, N 8.16. Found: C 62.96, H 6.37, N 8.09.

Compound 72 4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}3oxo-2H-1,4-benzoxazine ##STR93##

Prepared from Compound 71 by method K in 34% yield, mp 90°-101° C.; IR(KBr) 3355, 1501, 1468, 1402, 1244, 750 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.68(br t, 1H), 7.50-6.80(v br s, 1H), 7.35 (d, 1H, J=7.3 Hz), 7.20 (m, 4H),7.03 (m, 4H), 6.92 (d, 2H, J=8.4 Hz), 5.22 (d, 1H, J=16.5 Hz), 5.13 (d,1H, J=16.5 Hz), 5.00 (dd, 1H, J=4.2, 8.7 Hz), 4.21 (m, 2H), 2.72 (br t,2H), 2.51 (m, 2H), 2.38 (br s, 1H), 2.24 (br s, 1H). Anal. Calc'd forC₂₆ H₂₇ ClN₄ O₃. 2.5 HCl: C 54.77, H 5.22, N 9.83. Found: C 54.99, H5.34, N 9.79.

Compound 73 2-{2-3-(t-Butoxycarbonylaminomethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR94##

Prepared from 10488-22 (Reference Example 66) by method J in 48% yield,mp 98°-100° C.; MS (Cl) M⁺ 522, one Cl present; IR (KBr) 3351, 2927,1599, 1530, 1505, 1447, 1402, 1279, 1175, 1111, 1055, 939, 864 cm⁻¹ ; ¹H NMR (CDCl₃) δ 7.24 (m, 5H), 7.13 (m, 1H), 7.00 (m, 2H), 6.92 (m, 1H),6.83 (m, 3H), 5.18 (d, 1H, J=16.0 Hz), 5.07 (d, 1H, J=16.0 Hz), 4.93(dd, 1H, J=3.9, 9.2 Hz), 4.83 (br. s, 1H), 4.37-4.14 (brm, 4H), 2.58 (m,1H), 2.34 (m, 1H), 1.46 (s, 9H). Anal. Calc'd for C₂₉ H₃₁ Cl N₂ O₅. 0.3H₂ O: C 65.92, H 6.03, N 5.30. Found: C 65.95, H 5.99, N 5.22.

Compound 74 2-{2-3-(Aminomethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR95##

Prepared from Compound 73 by method K in quantitative yield, mp124°-129° C.; MS (Cl) MH⁺ 423;IR (KBr) 2886, 1599, 1501, 1402, 1265,1171, 1080, 1051, 885, 470 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.27 (m, 5H), 7.13(m, 1H), 7.00 (m, 2H), 6.95 (m, 2H), 6.90 (m, 2H), 6.83 (m, 2H), 5.17(d, 1H, J=16.2 Hz), 5.08 (d, 1H, J=16.2 Hz), 4.94 (dd, 1H, J=4.0, 9.2Hz), 4.26 (m, 2H), 3.82 (s, 2H), 2.59 (m, 1H), 2.34 (m, 1H). Anal.Calc'd for C₂₄ H₂₃ ClN₂ O₃.HCl 0.4 H₂ O: C 61.78, H 5.36, N 6.00. Found:C 61.78, H 5.36, N 5.83.

Compound 75 2-{2-4-(3-(t-Butoxycarbonylamino)propyl)phenoxy!ethyl}-4-(3-chlorobenzyl)--3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR96##

Prepared from 10488-22 (Reference Example 66) and 4-3-(N-t-butoxycarbonylamino)propyl!phenol by method L in 58% yield, mp75°-81° C.; MS (FAB) MH⁺ 551; IR (KBr) 3365, 2979, 2934, 1611, 1512,1503, 1468, 1398, 1366, 1302, 1279, 1242, 1022, 997, 922 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 7.24 (d, 4H, J=6.4 Hz), 7.12 (m, 2H), 7.08 (d, 1H, J=8.6 Hz),7.00 (m, 2H), 6.92 (m, 1H), 6.84 (m, 2H), 5.17 (d, 1H, J=16.0 Hz), 5.08(d, 1H, J=16.0 Hz), 4.94 (dd, 1H, J=3.9, 9.2 Hz), 4.21 (m, 2H), 3.14 (m,2H), 2.59 (m, 2H), 2.32 (m, 1H), 1.78 (m, 2H), 1.44 (s, 9H). Anal.Calc'd for C₃₀ H₃₃ ClN₂ O₅ : C 67.09, H 6.19, N 5.22. Found: C 67.46, H6.54, N 4.93.

Compound 76 2-{2-4-(3-Aminopropyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR97##

Prepared from Compound 75 by method K, mp 109°-111° C.; MS (Cl) MH⁺451;IR (KBr) 2936, 1674, 1609, 1514, 1466, 1400, 1302, 1111, 1049, 800,681 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.95 (brs, 2H), 7.36 (m, 4H), 7.21 (d,1H, J=6.8 Hz), 7.13 (d, 2H, J=8.5 Hz), 7.02 (m, 4H), 6.90 (d, 2H, J=8.5Hz), 5.19 (d, 1H, J=16.2 Hz), 5.13 (d, 1H, J=16.2 Hz), 5.00 (dd, 1H,J=4.2, 8.7 Hz), 4.19 (m, 2H), 2.75 (brs, 2H), 2.58 (brt, 2H, J=7.4 Hz),2.39 (m, 1H), 2.23 (m, 1H), 1.82 (m, 2H). Anal Calc'd for C₂₆ H₂₇ ClN₂O₃.HCl.H₂ O: C 61.78, H 5.98, N 5.54. Found: C 61.91, H 6.07, N 5.62.

Compound 77 2-{2- 4- (N,N-'Bis-tert-butoxycarbonyl)guanidinomethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR98##

Prepared by method L using intermediate 10488-22 (Reference Example 66)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)methyl guanidine in 52%yield, mp 74° C. shrinks, 89°-95° C. melts; MS (FAB) MH⁺ 665;IR (KBr)3334, 2979, 1723, 1690, 1501, 1396, 1368, 1325, 1248, 1057, 810 cm⁻¹ ; ¹H NMR (CDCl₃) δ 11.52 (s, 1H), 8.49 (br t, 1H), 7.24 (m, 4H), 7.13 (m,1H), 6.99 (m, 3H), 6.92 (m, 2H), 6.89 (d, 1H, J=8.5 Hz), 6.82 (d, 1H,J=7.5 Hz), 5.18 (d, 1H, J=16.0 Hz), 5.08 (d, 1H, J=16.0 Hz), 4.93 (dd,1H, J=3.9, 9.3 Hz), 4.54 (d, 2H, J=4.9 Hz), 4.25 (m, 2H), 2.59 (m, 1H),2.34 (m, 1H), 1.52 (s, 9H), 1.47 (s, 9H). Anal. Calc'd for C₃₅ H₄₁ ClN₄O₇.H₂ O: C 61.53, H 6.34, N 8.20. Found: C 61.50, H 6.26, N 8.03.

Compound 78 4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(guanidinylmethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR99##

Prepared from Compound 77 by method K in 37% yield, mp decomposes >61°C.; MS (Cl) MH⁺ 465;IR (KBr) 3338, 1501, 1398, 1246, 1051, 750 cm⁻¹ ; ¹H NMR (DMSO-d₆) δ 8.03 (br t, 1H, J=5.9 Hz), 7.35 (m, 5H), 7.23 (m, 5H),7.02 (m, 6H), 5.23 (d, 1H, J=16.5 Hz), 5.12 (d, 1H, J=16.5 Hz), 5.00(dd, 1H, J=4.2, 8.7 Hz), 4.29 (d, 2H, J=5.9 Hz), 4.22 (m, 2H), 2.40 (m,1H), 2.25 (m, 1H). Anal. Calc'd for C₂₅ H₂₅ ClN₄ O₃.HCl. H₂ O.0.1C6H14:C 58.23, H 5.61, N 10.61. Found: C 58.51, H 5.40, N 10.81.

Compound 79 2-{2-4-(2-Aminoethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR100##

Prepared from 10488-22 (Reference Example 66) and 4-2-(N--butoxycarbonylamino)ethyl!phenol by method J followed by method Kin quantitative yield mp 140.5°-143° C.; MS (Cl) MH⁺ 437;IR (KBr) 2930,1885, 1591,1503, 1466, 1437, 1398, 1323, 1182, 1138, 991, 879 cm⁻¹ ; ¹ HNMR (DMSO-d₆) δ 8.00 (br s, 3H), 7.35 (m, 3H), 7.20 (m, 3H), 7.03 (m,4H), 6.92 (d, 2H, J=8.6 Hz), 5.23 (d, 1H, J=16.5 Hz), 5.13 (d, 1H,J=16.4 Hz), 5.00 (dd, 1H, J=4.2, 8.7 Hz), 4.19 (m, 2H), 2.98 (m, 2H),2.82 (m, 2H), 2.39 (m, 1H), 2.22 (m, 1H). Anal. Calc'd for C₂₅ H₂₅ Cl N₂O₃.HCl: C 63.43, H 5.54, N 5.92. Found: C 63.26, H 5.46, N 5.86.

Compound 80 2-{2-4-(2-(N,N-'Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine##STR101##

Prepared from intermediate 11653-35B (Reference Example 87) andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Jin 57% yield, mp (dec)>69° C.; MS (FAB) MH⁺ 724;IR (KBr) 3329, 3119,3090, 2977, 2933, 2420, 2287, 1575, 1475, 1080, 1057, 927, 855, 701,576, 490 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.50 (br s, 1H), 8.37 (br s, 1H),7.88 (d, 1H, J=2.4 Hz), 7.82 (dd, 1H, J=2.6, 8.8 Hz), 7.28 (d, 2H, J=5.1Hz), 7.22 (s, 1H), 7.12 (m, 3H), 6.90 (d, 1H, J=8.8 Hz), 6.84 (d, 2H,J=8.5 Hz), 5.23 (d, 1H, J=16.4 Hz), 5.13 (d, 1H, J=16.3 Hz), 5.06 (dd,1H, J=3.4, 9.1 Hz), 4.23 (m, 2H), 3.63(q, 2H, J=5.4 Hz), 2.82 (t, 2H,J=7.2 Hz), 2.65 (m, 1H), 2.37 (m, 1H), 1.50 (s, 9H), 1.48 (s, 9H). Anal.Calc'd for C₃₆ H₄₂ Cl N₅ O₉.0.5 H₂ O: C 58.97, H 5.91, N 9.55. Found: C58.97, H 6.00, N 9.25.

Compound 81 2-{2- 4- 2-(tert-Butoxycarbonylamino)ethyl!phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine##STR102##

Prepared from intermediate 11653-35B (Reference Example 87) andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Jin 20% yield, mp 82°-85° C.; MS (Cl) MH⁺ 582;IR (KBr) 3366, 3085, 2975,2935, 1882, 1695, 1600, 1526, 1512, 1477, 1442, 1389, 1365, 1301, 1114,999, 853, 665 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 7.88 (d, 1H, J=2.42 Hz), 7.84(dd, 1H, J=8.82, 2.55 Hz), 7.28 (m, 4H), 7.22 (s, 1H), 7.12 (d, 2H,J=8.57 Hz), 6.90 (d, 1H, J=8.84 Hz), 6.85 (d, 1H, J=8.60 Hz), 5.23 (d,1H, J=16.2 Hz), 5.13 (d, 1H, J=16.3 Hz), 5.06 (dd, 1H, J=9.03, 3.94 Hz),4.53 (br s, 1H), 4.24 (m, 2H), 3.33 (m, 2H), 2.74 (t, 2H, J=6.86 Hz),2.62 (m, 1H), 2.37 (m, 1H), 1.44 (s, 9H). Anal. Calc'd for C₃₀ H₃₄ ClN₃O₇ : C 61.91, H 5.54, N 7.22. Found: C 61.58, H 5.80, N 7.36.

Compound 82 2-{2-4-(2-Aminoethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazinemonohydrochloride ##STR103##

Prepared from Compound 81 by method K in 46% yield, mp 79° C.-shrinks,92°-96° C.-melts; MS (Cl) MH⁺ 482;IR (KBr) 3392, 2933, 2021, 1474, 1441,1146, 1118, 928, 852, 701, 528 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.95 (br s,2H), 7.92 (d, 1H, J=2.5 Hz), 7.87 (m, 1H), 7.42 (s, 1H), 7.36 (m, 2H),7.24 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.5 Hz), 6.92 (d, 2H, J=8.5 Hz),5.30 (d, 1H, J=16.8 Hz), 5.18 (m, 2H), 4.22 (m, 2H), 2.98 (t, 2H, J=8.6Hz), 2.80 (t, 2H, J=8.6 Hz), 2.38 (m, 1H), 2.26 (m, 1H). Anal. Calc'dfor C₂₅ H₂₄ ClN₃ O₅.HCl. H₂ O: C 55.98, H 5.07, N 7.83. Found: C 55.92,H 4.80, N 7.82.

Compound 83 2-{2-4-(N,N-'Bis-tert-butoxycarbonylguanidinomethyl)phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine##STR104##

Prepared from intermediate 11653-35B (Reference Example 87) andN,N'-di-t-butoxycarbonyl-(4-hydroxyphenyl)methyl guanidine by method Jin 65% yield, mp 67.5° C.-shrinks, 84°-88° C.-melts. MS (FAB) MH⁺ 710;IR(KBr) 3730, 3326, 3122, 3089, 2978, 2932, 2413, 1720, 1640, 1615, 1503,1476, 1081, 931, 558 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.55 (br s, 1H), 8.59 (brs, 1H), 7.90 (d, 1H, J=2.5 Hz), 7.84 (dd, J=2.5, 8.8 Hz), 7.25 (m, 4H),7.10 (m, 1H), 6.86 (m, 4H), 5.22 (d, 1H, J=16.3 Hz), 5.30 (d, 1H, J=16.3Hz), 5.10 (dd, 1H, J=3.4, 9.1 Hz), 4.60 (m, 2H), 4.23 (m, 2H), 2.66 (m,1H), 2.38 (m, 1H), 1.51 (s, 9H), 1.47 (s, 9H). Anal. Calc'd for C₃₅ H₄₀ClN₅ O₉ : C 59.19, H 5.68, N 9.86. Found: C 59.10, H 6.07, N 9.74.

Compound 84 3,4-Dihydro-4-(3-chlorobenzyl)-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-7-nitro-3-oxo-2H-1,4-benzoxazinemonohydrochloride ##STR105##

Prepared from Compound 83 by method K in quantitative yield, mp(dec)>101° C.; MS (FAB) MH⁺ 524;IR (KBr) 3326, 3156, 2968, 2878, 1695,1665, 1599, 1513, 1473, 1441, 1389, 1178, 1148, 1022, 852, 472 cm⁻¹ ; ¹H NMR (DMSO-d₆) δ 7.93 (d, 0.5H, J=2.6 Hz), 7.89 (m, 1.5H), 7.62 (br t,1H), 7.43 (s, 1H), 7.40-6.65(v br s, 3H), 7.35 (m, 2H), 7.27 (d, 2H,J=8.6 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.92 (d, 2H, J=8.6 Hz), 5.33 (d, 1H,J=16.7 Hz), 5.20 (d, m, 2H, J=16.5 Hz), 4.22 (m, 2H), 3.32 (m, 2H), 2.73(t, 2H, J=7.3 Hz), 2.41 (m, 1H), 2.32 (m, 1H). Anal. Calc'd for C₂₆ H₂₆ClN₅ O₅.HCl H₂ O: C 53.99, H 5.05, N 12.11. Found: C 54.11, H 4.95, N12.01.

Compound 85 2-{2-4-(2-(N,N-Bis-tert-butoxycarbonyl)guanidinoethyl)phenoxy!ethyl}-4-(2-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine##STR106##

Prepared from intermediate 11653-58C (Reference Example 68) andN,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine in 85% yield,mp 69° C.-shrinks 90°-92° C.-melts; MS (FAB) MH⁺ 724;IR (KBr) 3329,3128, 2978, 2934, 1722, 1697, 1638, 1524, 1474, 1414, 1364, 1021, 933cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.47 (br s, 1H), 8.37 (br s, 1H), 7.91 (dd,1H, J=2.4, 8.8 Hz), 7.77 (d, 1H, J=2.5 Hz), 7.27 (m, 2H), 7.19 (brs,1H), 7.10 (m, 4H), 6.83 (d, 2H, J=8.6 Hz), 5.23 (d, 1H, J=17.9 Hz), 5.14(d, 1H, J=17.9 Hz), 5.09 (dd, 1H, J=4.1, 9.1 Hz), 4.20 (m, 2H), 3.63 (m,2H), 2.82 (t, 2H, J=7.1 Hz), 2.62 (m, 1H), 2.37 (m, 1H), 1.50 (s, 9H),1.48 (s, 9H). Anal. Calc'd for C₃₆ H₄₂ ClN₅ O₉ : C 59.71, H 5.85, N9.67. Found: C 59.38, H 6.04, N 9.63.

Compound 86 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonyl)guanidino)ethyl)phenoxy!ethyl}-4-(2-chlorobenzyl)-3,4-dihydro-7-nitro-3-oxo-2H-1,4-benzoxazine##STR107##

Prepared from intermediate 11653-24A (Reference Example 86) andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Lin 52% yield as a yellow foam, mp (dec)>85° C.; MS: FAB MH⁺ 724;IR (KBr)3335, 2979, 1637, 1527, 1390, 1341, 1156, 1059 cm⁻¹ ; ¹ H NMR (CDCl₃) δ11.48 (br s, 1H), 7.90 (d, 1H, J=2.50), 7.83 (dd, 1H, J=2.52, 8.85),7.45 (d, 1H, J=7.90), 7.26 (m, 1H), 7.19 (m, 2H), 7.14 (d, 1H, J=8.52),6.94 (d, 1H, J=7.68), 6.85 (d, 2H, J=8.50), 6.80 (d, 1H, J=8.90), 5.30(d, 2H, J=5.54), 5.08 (dd, 1H, J=5.02), 4.23 (m, 2H), 3.65 (m, 2H), 2.82(t, 2H, J=7.2), 2.65 (m, 1H), 2.39 (m, 1H), 1.50 (s, 9H), 1.48 (s, 9H).Anal. Calc'd for C₃₆ H₄₂ ClN₅ O₉ : C 59.71, H 5.85, N 9.67. Found: C59.48, H 5.89, N 9.52.

Compound 87 4-(2-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-7-nitro-3-oxo-2H-1,4-benzoxazinemonohydrochloride ##STR108##

Prepared from Compound 86 by method K in 79% yield, mp 120°-125° C.; MS(Cl) MH⁺ 524;IR (KBr) 3368, 3322, 3168, 2932, 2878, 1694, 1502, 1334,1234, 1028, 806 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.92 (m, 1.5H), 7.90 (d,0.5H, J=7.9 Hz), 7.55 (m, 2H), 7.40-6.50(v br s., 3H), 7.34 (t, 1H,J=7.5 Hz), 7.26 (t, 1H, J=7.5 Hz), 7.20 (d, 2H, J=8.6 Hz), 7.08 (m, 2H),6.92 (d, 2H, J=8.6 Hz), 5.28 (d, 1H, J=17.4 Hz), 5.22 (m, 1H), 5.16 (d,1H, J=17.4 Hz), 4.22 (m, 2H), 3.34 (m, 2H), 2.71 (t, 2H, J=7.6 Hz), 2.41(m, 1H), 2.35 (m, 1H). Anal. Calc'd for C₂₆ H₂₆ ClN₅ O₅.HCl.H₂ O: C53.99, H 5.05, N 12.11. Found C 53.75, H 5.23, N 12.09.

Compound 88 2-{2-4-(2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-4-(2-chlorobenzyl)-3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazine##STR109##

Prepared from intermediate 11653-44A (Reference Example 70) andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Lin 50% yield, mp 155° C.-shrinks, 160°-163° C.-melts. IR (KBr) 3345,3108, 2980, 2934, 1723, 1701, 1529, 1338, 1126, 878 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 11.48 (br s, 1H), 8.38 (br s, 1H), 7.91 (dd, 1H, J=2.5, 8.8Hz), 7.69 (d, 1H, J=2.5 Hz), 7.46 (dd, 1H, J=1.3, 9.1 Hz), 7.20 (m, 1H),7.12 (m, 4H), 7.01 (d, 1H, J=7.6 Hz), 6.83 (d, 2H, J=8.6 Hz), 5.31 (s,2H), 5.11 (dd, 1H, J=4.0, 8.9 Hz), 4.22 (m, 2H), 3.63 (m, 2H), 2.82 (t,2H, J=7.2 Hz), 2.65 (m, 1H), 2.39 (m, 1H), 1.50 (s, 9H), 1.48 (s, 1H).Anal. Calc'd for C₃₆ H₄₂ ClN₅ O₉ : C 59.71, H 5.85, N 9.67. Found: C59.89, H 5.84, N 9.61.

Compound 89 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)-phenoxy!ethyl}-6-nitro-4-(2-chlorobenzyl)-3-oxo-2H-1,4-benzoxazine##STR110##

Prepared from Compound 88 by method K in 90% yield, mp (dec)>85° C.; MS(Cl) MH⁺ 524; IR (KBr) 3335, 3156, 1651, 1524, 1515, 1446, 1343, 1269,1243, 1108, 746 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 7.94 (dd, 1H, J=2.5, 8.9 Hz),7.64 (d, 2H, J=2.6 Hz), 7.56 (d, 1H, J=7.8 Hz), 7.50-6.55(v. br. s.,3H), 7.30 (m, 4H), 7.19 (m, 3H), 6.90 (d, 2H, J=8.6 Hz), 5.31 (m, 2H),5.21 (d, 1H, J=17.2 Hz), 4.19 (m, 2H), 3.29 (m, 2H), 2.71 (t, 2H, J=7.7Hz), 2.44 (m, 1H), 2.35 (m, 1H). Anal. Calc'd for C₂₆ H₂₆ ClN₅ O₅.HCl.0.5 H₂ O: C 54.84 H 4.96, N 12.30. Found: C 54.87, H 4.94N 12.02.

Compound 90 3,4-Dihydro-2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-4-(3-nitrobenzyl)-7-nitro-3-oxo-2H-1,4-benzoxazine##STR111##

Prepared from intermediate 11653-85-B-1 (Reference Example 67) andN,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine by method Lin 41% yield, mp (dec)>84° C.; MS (Cl) MH⁺ 735; IR (KBr) 3331, 2979,2934, 1719, 1638, 1533, 1512, 1477, 1343, 1132, 812 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 11.48 (s, 1H), 8.37 (br.t., 1H), 8.16 (m, 1H), 8.12 (s, 1H),7.91 (d, 1H, J=2.4 Hz), 7.85 (dd, 1H, J=2.5, 8.9 Hz), 7.54 (m, 2H), 7.13(d, 2H, J=8.5 Hz), 6.89 (d, 1H, J=8.9 Hz), 6.83 (d, 1H, J=8.6 Hz), 5.34(d, 1H, J=16.6 Hz), 5.27 (d, 1H, J=16.7 Hz), 5.10 (dd, 1H, J=4.0, 8.9Hz), 4.24 (m, 2H), 3.63(q, 2H, J=7.0 Hz), 2.82 (t, 2H, J=7.2 Hz), 2.63(m, 1H), 2.38 (m, 1H), 1.62 (br. s., 1H), 1.50 (s, 9H), 1.48 (s, 9H).Anal. Calc'd for C₃₆ H₄₂ N₆ O₁₁ : C 58.85, H 5.76, N 11.44. Found: C58.73, H 5.77, N 11.34.

Compound 91 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-7-nitro-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR112##

Prepared from Compound 90 by method K, mp (dec)>90° C.; MS (Cl) MH⁺ 535;IR (KBr) 3336, 3155, 1696, 1602, 1528, 1390, 1343, 1244, 1179, 927, 743cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.23 (s, 1H), 8.15 (d, 1H, J=8.1 Hz), 7.89(m, 2H), 7.72 (d, 1H, J=7.7 Hz), 7.63 (t, 1H, J=7.9 Hz), 7.55 (br t,1H), 7.51-6.65(v br s., 3H), 7.31 (d, 1H, J=7.31 Hz), 7.20 (d, 2H, J=8.6Hz), 6.91 (d, 2H, J=8.6 Hz), 5.43 (d, 1H, J=16.6 Hz), 5.34 (d, 1H,J=17.3 Hz), 5.23 (dd, 1H, J=4.1, 8.7 Hz), 4.21 (m, 2H), 3.30 (m, 2H),2.71 (t, 2H, J=7.3 Hz), 2.41 (m, 1H), 2.30 (m, 1H). Anal. Calc'd for C₂₆H₂₆ N₆ O₇.HCl. 0.7 H₂ O: C 53.51, H 4.91, N 14.40. Found: C 53.87, H4.77, N 14.72.

Compound 92 6-Amino-4-(3-chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR113##

4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-6-nitro-3-oxo-2H-1,4-benzoxazine (0.3g) was warmed in ethanol (5 ml) and H₂ O (4 ml) until completely insolution. Iron powder (0.19 g, 6.8 eq) was stirred in followed by NH₄ Cl(0.02 g, 0.7 eq) and the reaction continued at reflux for 5 hours. Whilestill hot, the mixture was filtered through celite and the yellowfiltrate concentrated down to a yellow oil. After drying in vacuo at 80C.°, the product was collected as a yellow solid in 85% yield, mp(dec)>94° C.; MS (Cl) MH⁺ 494; IR (KBr) 3332, 1667, 1614, 1512, 1467,1396, 1243, 830, 774, 680 cm⁻¹ ; ¹ H NMR (DMSO-d₆ /CDCl₃) δ 7.66 (br s,1H), 7.58-6.50 (v br s, 3H), 7.36 (m, 4H), 7.20 (m, 3H), 6.91 (d, 2H,J=8.6 Hz), 6.74 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=2.2 Hz), 6.21 (dd, 1H,J=2.2, 8.4 Hz), 5.08 (d, 1H, J=16.7 Hz), 4.99 (d, 1H, J=16.5 Hz),5.12-4.78(v br s., 1H), 4.79 (dd, 1H, J=4.0, 8.9 Hz), 4.15 (m, 2H), 3.33(m, 2H), 2.71 (t, 2H, J=7.5 Hz), 2.30 (m, 1H), 2.18 (m, 1H). Anal.Calc'd for C₂₆ H₂₈ ClN₅ O₃.HCl.0.5 H₂ O: C 57.89, H 5.61, N 12.98.Found: C 57.64, H 5.48, N 12.63.

Compound 93 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-4-(4-nitrobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR114##

Prepared from intermediate 11653-173 (Reference Example 71) and andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Lin 61% yield, mp (dec)>78° C.; IR (KBr) 3331, 2977, 1722, 1689, 1638,1513, 1500, 1467, 1278, 922, 859 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.48 (br s.,1H), 8.37 (br t, 1H), 8.19 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz),7.13 (d, 2H, J=8.6 Hz), 7.03 (m, 2H), 6.92 (m, 1H), 6.85 (d, 2H, J=8.6Hz), 6.75 (d, 1H, J=7.9 Hz), 5.29 (d, 1H, J=16.7 Hz), 5.18 (d, 1H,J=16.7 Hz), 4.95 (dd, 1H, J=3.9, 9.3 Hz), 4.22 (m, 2H), 3.64 (m, 2H),2.81 (t, 2H, J=7.3 Hz), 2.58 (m, 1H), 2.35 (m, 1H), 1.50 (s, 9H), 1.48(s, 9H). Anal. Calc'd for C₃₆ H₄₃ N₅ O₉.0.5 H₂ O: C 61.88, H 6.35, N10.02. Found: C 62.07, H 6.32, N 9.85.

Compound 94 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-3,4-dihydro-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR115##

Prepared from intermediate 11653-180 (Reference Example 61) andN,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine by method Lin 64% yield, mp (dec)>144° C.; MS (FAB) MH⁺ 690; IR (KBr) 3333, 2979,1769, 1720, 1684, 1641, 1613, 1582, 1526, 1512, 1501, 1467, 1403, 1303,1279, 1208, 1020 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.50 (br s, 1H), 8.37 (br t,1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.58 (d, 1H, J=7.7 Hz), 7.54 (m, 1H),7.12 (d, 2H, J=8.6 Hz), 7.02 (m, 2H), 6.91 (m, 2H), 6.85 (d, 1H, J=8.6Hz), 6.79 (d, 1H, J=7.7 Hz), 5.25 (s, 2H), 4.98 (dd, 1H, J=3.9, 9.4 Hz),4.22 (m, 2H), 3.63 (m, 2H), 2.81 (t, 2H, J=7.3 Hz), 2.58 (m, 1H), 2.34(m, 1H), 1.50 (s, 9H), 1.48 (s, 9H). Anal. Calc'd for C₃₆ H₄₃ N₅ O₉.H₂O: C 61.09, H 6.41, N 9.89. Found: C 61.40, H 6.47, N 9.55.

Compound 95 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR116##

Prepared from Compound 94 by method K in 58% yield, mp (dec)>79° C.; MS(FAB) MH⁺ 490; IR (KBr) 3321, 3146, 1665, 1529, 1500, 1466, 1399, 1349,1322, 1279, 1249, 1154, 1097, 1063, 1022, 924, 810, 687, 468 cm⁻¹ ; ¹ HNMR (DMSO-d₆) δ 8.18 (s, 1H), 8.13 (d, 1H, J=7.9 Hz), 7.68 (m, 1H),7.60-6.40 (v br s, 3H), 7.39 (s, 1H), 7.20 (m, 2H), 7.08 (m, 3H), 6.98(m, 3H), 6.92 (d, 1H, J=8.4 Hz), 5.36 (d, 1H, J=18.7 Hz), 5.28 (d, 1H,J=17.0 Hz), 5.02 (m, 1H), 4.28 (t, 1H, J=6.6 Hz), 4.18 (m, 1H), 3.35 (m,3H), 2.72 (t, 2H, J=6.3 Hz), 2.40 (m, 1H), 2.27 (m, 1H). Anal. Calc'dfor C₂₆ H₂₇ N₅ O₅. 2.1 HCl: C 55.16, H 5.18, N 12.37. Found: C 55.08, H5.23, N 12.21.

Compound 96 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-7-nitro-4-(4-nitrobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR117##

Prepared from 12279-11 (Reference Example 62) by method L in 43% yieldand isolated as a yellow solid, mp (dec)>77° C.; MS (FAB) MH⁺ 735; IR(KBr) 3329, 3087, 2976, 2932, 2871, 1720, 1639, 1610, 1474, 1390, 1155,1022, 882, 577, 461 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.49 (br s, 1H), 8.37 (brt, 1H), 8.21 (d, 2H, J=8.7 Hz), 7.91 (d, 1H, J=2.5 Hz), 7.84 (dd, 1H,J=2.5, 8.9), 7.40 (d, 2H, J=8.6 Hz), 7.14 (d, 2H, J=8.6 Hz), 6.83 (dd,3H, J=2.5, 9.0 Hz), 5.35 (d, 1H, J=15.4 Hz), 5.25 (d, 1H, J=15.4 Hz),5.08 (dd, 1H, J=4.0, 8.9 Hz), 4.22 (m, 2H), 3.63 (m, 2H), 2.82 (t, 2H,J=7.4 Hz), 2.63 (m, 1H), 2.38 (m, 1H), 1.50 (s, 9H), 1.48 (s, 9H). Anal.Calc'd for C₃₆ H₄₂ N₆ O₁₁.C₃ H₆ O: C 59.03, H 6.10, N 10.60. Found: C58.96, H 6.17, N 10.54.

Compound 97 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-7-nitro-4-(4-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR118##

Prepared from Compound 96 by method K in quantitative yield, mp(dec)>141° C.; MS (FAB) MH⁺ 535; IR (KBr) 3323, 3158, 2948, 1702, 1667,1598, 1470, 1434, 1396, 1182, 1144, 1107, 1012, 995, 898, 860, 826 cm⁻¹; ¹ H NMR (DMSO-d₆) δ 8.22 (d, 2H, J=8.8 Hz), 7.92 (s, 1H), 7.89 (d, 1H,J=2.6 Hz), 7.61 (m, 3H), 7.60-6.65 (v br s, 2H), 7.23 (m, 4H), 6.94 (d,2H, J=8.6 Hz), 5.47 (d, 1H, J=17.3 Hz), 5.36 (d, 1H, J=17.3 Hz), 5.27(dd, 1H, J=8.8, 4.2 Hz), 4.23 (m, 2H), 3.35 (m, 2H), 2.74 (t, 2H, J=7.4Hz), 2.45 (m, 1H), 2.38 (m, 1H). Anal. Calc'd for C₂₆ H₂₆ N₆ O₇.HCl. 0.9H₂ O. 0.2 IPA: C 53.32, H 5.11, N 14.02. Found: C 53.07, H 4.84, N13.74.

Compound 98 2-{2-4-(2-(N,N-'Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-4-(2-nitrobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR119##

Prepared by method L using intermediate 11653-174-A (Reference Example73) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine in40% yield as a yellow solid, mp (dec)>65° C.; MS (Cl) MH⁺ 690; IR (KBr)3330, 3151, 2978, 2934, 1723, 1694, 1616, 1528, 1502, 1302, 1277, 1228,1087, 1022, 933, 880, 562, 464 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.40 (br s,1H), 8.36 (br s, 1H), 8.18 (d, 1H, J=8.12 Hz), 7.42 (m, 2H), 7.10 (m,2H), 6.96 (m, 4H), 6.85 (m, 1H), 6.73 (d, 2H, J=8.27 Hz), 5.50 (d, 2H,J=17.95 Hz), 4.95 (dd, 1H, J=9.59, 4.21 Hz), 4.16 (m, 2H), 3.56 (m, 2H),2.77 (m, 2H), 2.57 (m, 1H), 2.35 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H).Anal. Calc'd for C₃₆ H₄₃ N₅ O₉. 0.9 H₂ O: C 61.25, H 6.40, N 9.92.Found: C 60.79, H 6.76, N 10.39.

Compound 99 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-3,4-dihydro-7-methoxy-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR120##

Prepared by method L using intermediate 12279-18-A (Reference Example63) and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)ethyl guanidine in83% yield, mp (dec)>71° C.; MS (FAB) MH⁺ 720; IR (KBr) 3329, 2977, 2934,1722, 1683, 1639, 1532, 1413, 1350, 1330, 1247, 1164, 1057, 916, 729,529 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.48 (s, 1H), 8.37 (br s, 1H), 8.15 (s,1H), 8.12 (s, 1H), 7.53 (m, 2H), 7.13 (d, 2H, J=8.62 Hz), 6.86 (d, 2H,J=8.62 Hz), 6.68 (d, 1H, J=8.88 Hz), 6.61 (d, 1H, J=2.72 Hz), 6.47 (dd,1H, J=8.85, 2.70 Hz), 5.21 (s, 2H), 4.96 (dd, 1H, J=9.36, 3.95 Hz), 4.23(m, 2H), 3.74 (s, 3H), 3.63 (m, 2H), 2.81 (t, 2H, J=7.22 Hz), 2.57 (m,1H), 2.33 (m, 1H), 1.50 (s, 9H), 1.48 (s, 9H). Anal. Calc'd for C₃₇ H₄₅N₅ O₁₀ : C 61.74, H 6.30, N 9.73. Found: C 61.24, H 6.43, N 9.76.

Compound 100 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-7-methoxy-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR121##

Prepared from Compound 99 by method K in 87% yield, mp (dec)>68° C.; MS(Cl) MH⁺ 520; IR (KBr) 3317, 3147, 2930, 1466, 1407, 1357, 1324, 1309,1163, 1135, 922, 798, 669, 530 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.16 (s, 1H),8.13 (d, 1H, J=8.28 Hz), 7.66 (m, 2H), 7.60 (t, 2H, J=7.30 Hz),7.53-6.70(v br s, 2H), 7.20 (d, 2H, J=8.48 Hz), 7.01 (d, 1H, J=8.92 Hz),6.92 (d, 2H, J=8.48 Hz), 6.69 (d, 1H, J=2.79 Hz), 6.55 (dd, 1H, J=2.70,8.88 Hz), 5.28 (d, 2H, J=2.72 Hz), 4.98 (dd, 1H, J=4.05, 8.81 Hz), 4.20(m, 2H), 3.68 (s, 3H), 3.32 (m, 2H), 2.71 (t, 2H, J=7.16 Hz)2.37 (m,1H), 2.23 (m, 1H). Anal. Calc'd for C₂₇ H₂₉ N₅ O₆.HCl. 0.5 H₂ O: C57.39, H 5.53, N 12.39. Found: C 57.71, H 5.90, N 11.99.

Compound 101 4-(3-Aminobenzyl)-2-{2-4-(2-(N,N'-bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine ##STR122##

Prepared by method L using intermediate 12279-13-A (Reference Example65) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine, andisolated by flash chromatography, eluting with acetone/hexane in 55%yield as a white solid, mp (dec)>68° C.; MS (FAB) MH⁺ 660; IR (KBr)3335, 2977, 1722, 1685, 1638, 1512, 1500, 1466, 1408, 1366, 1329, 1244,1155, 1131, 1057, 809, 749, 688 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.48 (s, 1H),8.37 (br t, 1H), 7.12 (m, 3H), 6.95 (m, 2H), 6.87 (m, 4H), 6.85 (d, 1H,J=8.48 Hz), 6.64 (d, 1H, J=7.54 Hz), 6.56 (d, 1H, J=11.1 Hz), 5.07 (dd,2H, J=15.97, 24.50 Hz), 4.93 (dd, 1H, J=3.83, 5.49 Hz), 4.23 (m, 2H),3.62 (m, 4H), 2.81 (t, 2H, J=7.16 Hz), 2.56 (m, 1H), 2.33 (m, 1H), 1.50(s, 9H), 1.48 (s, 9H). Anal. Calc'd for C₃₆ H₄₅ N₅ O₇ : C 65.54, H 6.87N10.61. Found: C 65.43, H 6.92, N 10.38.

Compound 102 2-{2-4-(2-(N,N'-Bis-tert-butoxycarbonylguanidino)ethyl)phenoxy!ethyl}-3,4-dihydro-6-fluoro-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR123##

Prepared by method L using intermediate 12279-21 (Reference Example 64)and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine in 77%yield, mp (dec) >69° C.; MS (FAB) MH⁺ 708;IR (KBr) 3330, 2978, 1696,1638, 1533, 1507, 1453, 1415, 1350, 1249, 1155, 948, 670 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 11.47 (br s, 1H), 8.37 (brt, 1H), 8.16 (d, 1H, J=7.1 Hz), 8.11(br s, 1H), 7.53 (m, 2H), 7.14 (d, 2H, J=8.6 Hz), 6.98 (dd, 1H, J=5.1,8.9 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.70 (m, 1H), 6.51 (dd, 1H, J=2.8, 9.4Hz), 5.21 (d, 1H, J=16.4 Hz), 5.20 (d, 1H, J=16.4 Hz), 4.95 (dd, 1H,J=4.0, 9.3 Hz), 4.22 (m, 2H), 3.64 (m, 2H), 2.81 (t, 2H, J=7.1 Hz), 2.63(m, 1H), 2.34 (m, 1H), 1.50 (s, 9H), 1.48 (s, 9H). Anal. Calc'd for C₃₆H₄₂ FN₅ O₉. 1.5 H₂ O: C 60.41, H 6.34, N 9.78. Found: C 60.36, H 6.17, N10.06.

Compound 103 2- 2-{4-2-(t-Butoxycarbonylamino)ethyl!phenoxy}ethyl!-4-(4-carbomethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR124##

Prepared from intermediate 11758-71-2 (Reference Example 81) and 4-2-(N-t-butoxycarbonylamino)-ethyl!phenol by method L to afford productas a white solid in 69% yield, mp 110°-112° C.; ¹ H NMR (CDCl₃) δ 8.00(d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H),6.98-7.04 (m, 2H), 6.89-6.95 (m, 3H), 6.78 (dd, J=1.3, 8.5 Hz, 1H), 5.21(br s, 2H), 4.96 (dd, J=4.0, 9.5 Hz, 1H), 4.54 (br s with shoulders,1H), 4.15-4.30 (m, 2H), 3.90 (s, 3H), 3.31-3.36 (m, 2H), 2.74 (t, J=6.7Hz, 2H), 2.53-2.63 (m, 1H), 2.33 (ddt, J=14.1, 9.5, 4.8 Hz, 1H), 1.44(s, 9H). ¹³ C NMR (CDCl₃) δ 166.7, 166.4, 157.3, 155.9, 144.2, 141.3,131.3, 130.2 (CH), 129.8 (CH), 129.5, 128.7, 126.5 (CH), 124.3 (CH),122.9 (CH), 117.5 (CH), 115.3 (CH), 114.7 (CH), 76.6, 73.9 (CH), 63.1(CH₂), 52.1 (CH₃), 45.2 (CH₂), 41.9 (CH₂), 35.3 (CH₂), 30.4 (CH₂), 28.4(CH₃). IR 3376, 1713, 1684 cm⁻¹. MS (FAB) 561 (MH⁺), 461, 324 (base).Anal. Calc'd. for C₃₂ H₃₆ N₂ O₇ : C, 68.56; H, 6.47; N, 5.00. Found: C,68.16; H, 6.45; N, 4.90.

Compound 104 2-{2-4-(2-Aminoethyl)phenoxy!ethyl}-4-(4-carbomethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR125##

Prepared from Compound 103 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl. The resulting solid was trituratedwith ether to afford product as a white powder (182 mg; 88% yield;mp=164°-165° C.). ¹ H NMR (DMSO-d₆) δ 8.40 (br s, 3H), 7.98 (d, J=8.2Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 6.77-7.01 (m,6H), 5.21 (s, 2H), 4.94 (dd, J=4.0, 9.3 Hz, 1H), 4.19-4.27 (m, 2H), 3.90(s, 3H), 3.06-3.12 (m, 2H), 2.90-2.96 (m, 2H), 2.51-2.60 (m, 1H),2.29-2.37 (m, 1H). ¹³ C NMR (DMSO-d₆) δ 165.9, 165.6, 157.0, 143.4,140.7, 129.5 (CH), 129.2 (CH), 128.8, 128.5, 127.9, 125.8 (CH), 123.7(CH), 122.3 (CH), 116.8 (CH), 114.7 (CH), 114.2 (CH), 73.1 (CH), 62.5(CH₂), 51.5 (CH₃), 44.4 (CH₂), 40.4 (CH₂), 32.2 (CH₂), 29.6 (CH₂). IR2700-3200 (br), 1722, 1705, 1680 cm⁻¹. MS 461 (MH⁺). Anal. Calc'd. forC₂₇ H₂₈ N₂ O₅ /C₂ HF₃ O₂ : C, 60.62; H, 5.09; N, 4.88. Found: C, 60.31;H, 5.07; N, 4.78.

Compound 105 2- 2-{4-2-(t-Butoxycarbonylamino)ethyl!phenoxy}ethyl!-4-(3-carbomethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR126##

Prepared from intermediate 11758-93-2A (Reference Example 82) and 4-2-(N-t-butoxycarbonylamino)ethyl!phenol, by method L and isolated as awhite solid, 66.2% yield, mp 112°-113° C.; ¹ H NMR (CDCl₃) δ 7.93-7.95(m, 2H), 7.38-7.41 (m, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.88-7.02 (m, 3H),6.86 (d, J=8.5 Hz, 2H), 6.81 (dd, J=1.5, 7.7 Hz, 1H), 5.20 (s, 2H), 4.96(dd, J=4.0, 9.4 Hz, 1H), 4.51 (br s, 1H), 4.18-4.26 (m, 2H), 3.90 (s,3H), 3.32-3.35 (br m, 2H), 2.73 (t, J=6.5 Hz, 2H), 2.55-2.60 (m, 1H),2.32-2.38 (m, 1H), 1.43 (s, 9H). IR 3370, 1724, 1688 cm⁻¹. MS (FAB) 561(MH⁺), 324. Anal. Calc'd. for C₃₂ H₃₆ N₂ O₇ : C, 68.56; H, 6.47; N,5.00. Found: C, 68.37; H, 6.63; N, 4.88.

Compound 106 2-{2-4-(2-Aminoethyl)phenoxy!ethyl}-4-(3-carbomethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR127##

Prepared from Compound 105 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated as a cream-coloredsolid, 92% yield, mp=112°-114.5° C.; ¹ H NMR (DMSO-d₆) δ 7.90 (br s,1H), 7.86 (d, J=7.5 Hz, 1H), 7.77 (br s, 3H), 7.47-7.54 (m, 2H), 7.19(d, J=8.5 Hz, 2H), 7.00-7.08 (m, 4H), 6.95 (d, J=8.5 Hz, 2H), 5.26 (s,2H), 5.00 (dd, J=4.0, 8.9 Hz, 1H), 4.19-4.23 (m, 2H), 3.84 (s, 3H), 3.02(t, J=7.8 Hz, 2H), 2.79 (t, J=7.8 Hz, 2H), 2.35-2.40 (m, 1H), 2.23-2.28(m, 1H). IR 2900-3100 (br), 1717, 1683 cm⁻¹. MS 461 (MH⁺). Anal. Calc'd.for C₂₇ H₂₈ N₂ O₅ /C₂ HF₃ O₂ : C, 60.62; H, 5.09; N, 4.88. Found: C,60.27; H, 5.31; N, 4.68.

Compound 107 2- 2-{4-2-(t-Butoxycarbonylamino)ethyl!phenoxy}ethyl!-4-(2-carboethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR128##

Prepared from intermediate 11758-82-2 (Reference--Example 83) and 4-2-(N-t-butoxycarbonylamino)-ethyl!phenol, by method L and isolated as awhite solid in 76.9% yield, mp 103°-105° C.; ¹ H NMR (CDCl₃) δ 8.07 (dd,J=1.5, 7.6 Hz, 1H), 7.41 (dt, J=1.5, 7.6 Hz, 1H), 7.32 (dt, J=0.9, 7.6Hz, 1H), 7.10 (d, J=8.6 Hz, 2H), 6.95-7.07 (m, 3H), 6.85-6.92 (m, 3Hwith a 2H doublet (J=8.6 Hz) at δ 6.87), 6.72 (dd, J=1.4, 8.0 Hz, 1H),5.63 (d, J=17.9 Hz, 1H), 5.54 (d, J=17.9 Hz, 1H), 4.97 (dd, J=3.9, 9.4Hz, 1H), 4.52 (br s, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.20-4.28 (m, 2H),3.32-3.36 (br m, 2H), 2.74 (t, J=6.8 Hz, 2H), 2.56-2.69 (m, 1H), 2.36(ddt, J=14.4, 9.3, 4.8 Hz, 1H), 1.43 (t, J=7.1 Hz, 3H), 1.42 (s, 9H). ¹³C NMR δ 166.9, 166.4, 157.4, 155.9, 144.2, 137.7, 132.8 (CH), 131.5(CH), 131.3, 129.8 (CH), 129.0, 128.5, 127.1 (CH), 125.6 (CH), 124.1(CH), 122.9 (CH), 117.3 (CH), 115.6 (CH), 114.7 (CH), 73.7 (CH), 63.3(CH₂), 61.2 (CH₂), 50.9, 44.5 (CH₂), 41.9 (CH₂), 35.3 (CH₂), 30.4 (CH₂),28.4 (CH₃), 14.4 (CH₃).

Compound 108 2-{2-4-(2-Aminoethyl)phenoxy!ethyl}-4-(2-carboethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR129##

Prepared from Compound 107 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated as a white powder in94.5% yield, mp 107.5°-109° C.;¹ H NMR (DMSO-d₆) δ 7.99 (dd, J=1.5, 6.2Hz, 1H), 7.75 (br s, 3H), 7.39-7.53 (m, 2H), 7.18 (d, J=8.6 Hz, 2H),7.02-7.10 (m, 3H), 6.92-6.99 (m, 3H with a 2H doublet at δ 6.94), 6.81(d, J=8.0 Hz, 1H), 5.51 (d, J=17.5 Hz, 1H), 5.39 (d, J=17.5 Hz, 1H),5.04 (dd, J=4.1, 8.7 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.18-4.23 (m, 2H),2.90-3.02 (m, 2H), 2.75-2.81 (m, 2H), 2.28-2.45 (m, 2H), 1.37 (t, J=7.1Hz, 3H). IR 2975-3100 (br), 1690 (sh), 1680 cm⁻¹. MS 475 (MH⁺). Anal.Calc'd. for C₂₈ H₃₀ N₂ O₅ /1.0C₂ HF₃ O₂ /1.5H₂ O: C, 58.53; H, 5.57; N,4.55. Found: C, 58.48; H, 5.44; N, 4.55.

Compound 109 4-{2-2-(4-(2-(t-Butoxycarbonylamino)ethyl)phenoxy)!ethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR130## Method O

Compound 103 (150 mg, 1 eq) and 1N NaOH (2.5 eq) in methanol (10 mL)were heated in an oil bath at 50° C. for 26 h. After evaporation of themethanol, the residue was diluted with water (20 mL), cooled to 0° C.,and acidified with 1N citric acid (1 mL). The precipitate was collected,washed with water and dried to give product as a white solid in 89%yield, mp=147°-148° C.; ¹ H NMR (DMSO-d₆) δ 8.04 (d, J=8.1 Hz, 2H), 7.34(d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 6.75-7.04 (m, 6H), 5.22 (brs, 2H), 4.96 (dd, J=3.8, 9.0 Hz, 1H), 4.55 (br s, 1H), 4.10-4.28 (m,2H), 3.31-3.36 (m, 2H), 2.73 (t, J=6.3 Hz, 2H), 2.55-2.61 (m, 1H), 2.34(ddt, J=14.1, 9.8, 5.1 Hz, 1H), 1.43 (s, 9H). IR 3300-3350 (br), 1688(br) cm⁻¹. MS (FAB) 547 (MH⁺), 447 (M-Boc)⁺, 310 (base). Anal. Calc'd.for C₃₁ H₃₄ N₂ O₇ : C, 68.12; H, 6.27; N, 5.12. Found: C, 67.71; H,6.47; N, 5.00.

Compound 110 4-{3,4-Dihydro-2-2-(4-(2-aminoethyl)phenoxy)!ethyl-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR131##

Prepared from Compound 109 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated a white powder in 98%yield, mp 195°-197° C.; ¹ H NMR (DMSO-d₆) δ 12.97 (br s, 1H), 7.90 (d,J=8.2 Hz, 2H), 7.77 (br s, 3H), 7.38 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.3Hz, 2H), 6.97-7.05 (m, 4H), 6.95 (d, J=8.3 Hz, 2H), 5.28 (d, J=16.3 Hz,1H), 5.20 (d, J=16.3 Hz, 1H), 5.00 (dd, J=4.0, 8.7 Hz, 1H), 4.18-4.22(m, 2H), 2.98-3.02 (m, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.35-2.40 (m, 1H),2.23-2.28 (m, 1H). ¹³ C NMR δ 166.9, 165.8, 157.2, 143.6, 141.6, 129.8(CH), 129.7 (CH), 129.3, 128.3, 126.6 (CH), 123.9 (CH), 122.8 (CH),117.0 (CH), 115.7 (CH), 114.7 (CH), 73.0 (CH), 63.1 (CH₂), 43.7 (CH₂),39.9 (CH₂), 31.9 (CH₂), 29.4 (CH₂). IR 3000-3200 (br), 1681, 1503 cm⁻¹.MS 447 (MH⁺), 429 (M--OH)⁺. Anal. Calc'd. for C₂₆ H₂₆ N₂ O₅ /C₂ HF₃ O₂/0.5H₂ O: C, 59.05; H, 4.96; N, 4.92. Found: C, 58.96; H, 4.71; N, 4.76.

Compound 111 3-{3,4-Dihydro-2-2-(4-(2-(-t-butoxycarbonylamino)ethyl)phenoxy)!ethyl-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR132##

Prepared from Compound 105 by method 0 and isolated as a white glass in92% yield, mp76°-78° C.; ¹ H NMR (DMSO-d₆) δ 7.87 (br s, 1H), 7.82 (d,J=7.3 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.47 (q, J=7.4 Hz, 1H), 7.10 (d,J=8.5 Hz, 2H), 6.97-7.07 (m, 4H), 6.87 (d, J=8.5 Hz, 2H), 6.85 (br s,1H), 5.24 (s, 2H), 4.98 (dd, J=4.1, 8.8 Hz, 1H), 4.15-4.19 (m, 2H),3.06-3.10 (br q, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.32-2.37 (m,1H), 2.20-2.25 (m, 1H), 1.36 (s, 9H). IR 2800-3100 (br), 1704, 1700 (sh)cm⁻¹. MS 547 (MH⁺), 473 (base). Anal. Calc'd. for C₃₁ H₃₄ N₂ O₇ /0.5 H₂O: C, 67.01; H, 6.35; N, 5.04. Found: C, 67.03; H, 6.44; N, 4.95.

Compound 112 3-{3,4-Dihydro-2-2-(4-(2-aminoethyl)phenoxy)!ethyl-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR133##

Prepared from Compound 111 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated as white crystals in92% yield, mp 193°-195° C.; ¹ H NMR (DMSO-d₆) δ 13.03 (br s, 1H), 7.87(br s, 1H), 7.83 (d, J=7.4 Hz, 1H), 7.77 (br s, 3H), 7.51 (d, J=7.9 Hz,1H), 7.47 (q, J=7.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.04-7.07 (m, 2H),6.98-7.01 (m, 2H), 6.94 (d, J=8.5 Hz, 2H), 5.24 (s, 2H), 4.98 (dd,J=4.2, 8.8 Hz, 1H), 4.17-4.20 (m, 2H), 2.98-3.03 (m, 2H), 2.78 (t, J=7.8Hz, 2H), 2.36-2.43 (m, 1H), 2.21-2.34 (m, 1H). IR 2800-3200 (br), 1677,1636 cm⁻¹. MS 447 (MH⁺), 429, 194 (base). Anal. Calc'd. for C₂₆ H₂₆ N₂O₅ /C₂ HF₃ O₂ /0.5H₂ O: C, 59.05; H. 4.96; N, 4.92. Found: C, 58.74; H,4.87; N, 4.69.

Compound 113 2-{2-2-(4-(2-(-t-butoxycarbonylamino)ethyl)phenoxy)!ethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR134##

Prepared from Compound 107 by method O and isolated as a white powder in93.5% yield, mp 156°-159° C.; ¹ H NMR (CDCl₃ /DMSO-d₆) δ 8.13 (d, J=7.4Hz, 1H), 7.32-7.40 (m, 3H with 1H exchangeable), 7.11 (d, J=8.0 Hz, 2H),6.97-7.05 (m, 3H), 6.86 (d, J=8.0 Hz, 2H), 6.72-6.85 (m, 2H), 5.61 (d,J=18.1 Hz, 1H), 5.53 (d, J=18.1 Hz, 1H), 4.91 (dd, J=3.7, 9.3 Hz, 1H),4.65 (br s, 1H), 4.14-4.22 (m, 2H), 3.23-3.28 (br m, 2H), 2.68 (t, J=7.0Hz, 2H), 2.47-2.51 (m, 1H), 2.25-2.33 (m, 1H), 1.38 (s, 9H). IR3350-3500 (br), 2950, 1687, 1512 cm⁻¹. MS (FAB) 547 (MH⁺), 447 (base),310. Anal. Calc'd. for C₃₁ H₃₄ N₂ O₇ /0.50H₂ O: C, 67.01; H, 6.35; N,5.04. Found: C, 67.24; H, 6.56; N, 5.02.

Compound 114 2-{2-2-(4-(2-Aminoethyl)phenoxy)!ethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-4-yl}methylbenzoicacid ##STR135##

Prepared from Compound 113 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated as a white solid in76.8% yield, mp 132°-133° C.; ¹ H NMR (DMSO-d₆) δ 8.00 (d, J=6.4 Hz,1H), 7.74 (br s, 3H), 7.47 (t, J=6.5 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H),7.18 (d, J=2H), 6.91-7.09 (m, 6H with a 2H doublet (J=8.5 Hz) at δ6.95), 6.79 (d, J=7.3 Hz, 1H), 5.53 (d, J=18.4 Hz, 1H), 5.42 (d, J=18.4Hz, 1H), 5.04 (dd, J=4.0, 8.5 Hz, 1H), 4.18-4.24 (m, 2H), 2.95-3.09 (m,2H), 2.75-2.81 (m, 2H), 2.23-2.42 (m, 2H). IR 2950-3200 (br), 1683, 1514cm⁻¹. MS 447 (MH⁺), 138 (base). Anal. Calc'd. for C₂₆ H₂₆ N₂ O₅/1.0C2HF3O2/0.25 H₂ O: C, 59.52; H, 4.91; N, 4.96. Found: C, 59.43; H,4.91; N, 4.80.

Compound 115 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(4-carbomethoxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR136##

Prepared by by methods L using intermediate 11758-71-2 (ReferenceExample 81) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethylguanidine and isolated, after chromatography (eluting withEtOAc/hexanes), as a white glass, mp 68°-71° C.; ¹ H NMR (CDCl₃) δ 11.45(br s, 1H), 8.37 (br s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz,2H), 7.13 (d, J=8.6 Hz, 2H), 6.74-7.01 (m, 6H with a 2H doublet (J=8.6Hz) at 8 6.85), 5.23 (d, J=16.1 Hz, 1H), 5.16 (d, J=16.1 Hz, 1H), 4.95(dd, J=3.8, 9.5 Hz, 1H), 4.19-4.28 (m, 2H), 3.90 (s, 3H), 3.61-3.65 (m,2H), 2.81 (t, J=7.2 Hz, 2H), 2.55-2.63 (m, 1H), 2.31-2.38 (m, 1H), 1.50(s, 9H), 1.48 (s, 9H). IR 2950-3300 (br), 1724, 1688, 1639 cm⁻¹. MS(FAB) 703 (MH⁺), 503 (base). Anal. Calc'd. for C₃₈ H₄₆ N₄ O₉ /0.5H₂ O:C, 64.12; H, 6.66; N, 7.87. Found: C, 63.73; H, 6.87; N, 8.31.

Compound 116 2-{2- 4-2-(t-Butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-4-(4-carboxybenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR137##

Prepared from Compound 115 by method O. The resulting white semisolidwas collected, washed with water and dried. NMR shows ˜10% methyl esterpresent. ¹ H NMR (DMSO-d₆) δ 7.89 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz,2H), 6.88-7.08 (m, 8H), 5.27 (d, J=16.6 Hz, 1H), 5.19 (d, J=16.6 Hz,1H), 5.00 (dd, J=4.0, 8.7 Hz, 1H), 3.50-3.61 (m, 2H), 2.65-2.69 (m, 2H),2.35-2.45 (m, 1H), 2.21-2.30 (m, 1H), 1.37 (s, 9H). MS (FAB) 589 (MH⁺),489 (base).

Compound 117 4-(4-Carboxybenzyl)-2-{2- 4-2-(guanidino)ethyl!phenoxy!ethyl)}-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR138##

Prepared from Compound 116 by method K using trifluoroacetic acid withanisole present, instead of IPA/HCl and isolated to give an off-whitesolid, in 67% yield mp 197°-199° C.; ¹ H NMR (DMSO-d₆) δ 7.91 (d, J=8.3Hz, 2H), 7.76 (br s, 1H), 7.51 (brt, J=5 Hz, 1H), 7.40 (d, J=8.3 Hz,2H), 7.19 (d, J=8.5 Hz, 2H), 6.92-7.09 (m, 9H), 5.29 (d, J=17.0 Hz, 1H),5.23 (d, J=17.0 Hz, 1H), 5.01 (dd, J=4.1, 8.6 Hz, 1H), 4.18-4.23 (m,2H), 3.30-3.39 (m, 2H), 3.01 (br s, 1H), 2.62-2.81 (m, 2H), 2.35-2.43(m, 1H), 2.20-2.31 (m, 1H). IR 3000-3400 (br), 1676, 1501 cm⁻¹. MS (FAB)489 (MH⁺). Anal. Calc'd. for C₂₇ H₂₈ N₄ O₅ /1.0 C₂ HF₃ O₂ /0.5 H₂ O: C,56.95; H, 4.94; N, 9.16. Found: C, 57.32; H, 4.96; N, 8.78.

Compound 118 Methyl 4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-yl!ethoxy}phenylacetate ##STR139##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with methyl-4-hydroxyphenylacetate atreflux overnight, and isolating a white solid in 38% yield, mp 94°-95°C.; ¹ H NMR (CDCl₃) δ 7.13-7.25 (m, 5H), 7.03-7.11 (m, 1H), 6.81-7.01(m, 6H), 5.17 (d, J=16.2 Hz, 1H), 5.08 (d, J=16.2 Hz, 1H), 4.94 (dd,J=3.9, 9.4 Hz, 1H), 4.16-4.30 (m, 2H), 3.67 (s, 3H), 3.57 (s, 2H),2.53-2.64 (m, 1H), 2.33 (ddt, J=9.6, 14.5, 4.8 Hz, 1H). IR 1736, 1673,1502 cm⁻¹. MS 466 (MH⁺), 300 (base). Anal. Calc'd. for C₂₆ H₂₄ ClNO₅ :C, 67.02; H, 5.19; N, 3.01. Found: C, 66.78; H, 5.20; N, 2.94.

Compound 119 4-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-yl!ethoxy}phenylacetic acid ##STR140##

Prepared from Compound 118 by method O but was acidified withconcentrated HCL to afford the acid as a white solid in 95% yield,mp144°-145° C.; ¹ H NMR (DMSO-d₆) δ 7.19-7.24 (m, 5H), 7.11-7.13 (m,1H), 6.88-7.01 (m, 5H), 6.83 (d, J=7.3 Hz, 1H), 5.16 (d, J=16.3 Hz, 1H),5.07 (d, J=16.3 Hz, 1H), 4.93 (dd, J=5.4, 9.4 Hz, 1H), 4.19-4.23 (m,2H), 3.61 (s, 2H), 2.51-2.58 (m, 1H), 2.31-2.34 (m, 1H). IR 3000-3200(br), 1714, 1609 cm⁻¹. MS 452 (MH⁺). Anal. Calc'd. for C₂₅ H₂₂ ClNO₅ :C, 66.45; H, 4.91; N, 3.10. Found: C, 66.15; H, 4.66; N, 3.03.

Compound 120 Methyl 3-{4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl}propionate##STR141##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) withmethyl-3-(4-hydroxyphenyl)propionate at reflux overnight, and isolatinga white solid in 45% yield, mp 88°-89° C.; ¹ H NMR (CDCl₃) δ 7.14-7.25(m, 3H), 7.10 (d, J=8.6 Hz, 2H), 6.93-7.00 (m, 4H), 6.80-6.86 (m, 3H),5.15 (d, J=16.3 Hz, 1H), 5.09 (d, J=16.3 Hz, 1H), 4.94 (dd, J=4.0, 9.8Hz, 1H), 4.18-4.23 (m, 2H), 3.67 (s, 3H), 2.89 (t, J=7.8 Hz, 2H),2.52-2.62 (m, 3H), 2.21-2.28 (m, 1H). IR 1734, 1677, 1502 cm⁻¹. MS 480(MH⁺). Anal. Calc'd. for C₂₇ H₂₆ ClNO₅ /0.25 H₂ O: C, 66.94; H, 5.51; N,2.89. Found: C, 66.75; H, 5.36; N, 2.82.

Compound 121 3-{4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl}propionicacid ##STR142##

Prepared from Compound 120 by method O but was acidified with conc. HCLand isolated as a white solid in 90% yield, mp 141°-143° C.; ¹ H NMR(DMSO-d₆) δ 7.30-7.41 (m, 3H), 7.20-7.23 (m, 1H), 7.16 (d, J=8.1 Hz,2H), 6.93-7.10 (m, 4H), 6.87 (d, J=8.1 Hz, 2H), 5.23 (d, J=16.0 Hz, 1H),5.15 (d, J=16.0 Hz, 1H), 5.00 (dd, J=4.2, 8.9 Hz, 1H), 4.10-4.21 (m,2H), 2.68-2.75 (m, 3H), 2.30-2.52 (m, 3H), 2.12-2.27 (m, 1H). IR2900-3100 (br), 1721, 1686, 1502 cm⁻¹. MS 466 (MH⁺), 300 (base). Anal.Calc'd. for C26H24ClNO5/0.5 H2O: C, 65.75; H, 5.31; N, 2.95. Found: C,65.97; H, 5.05; N, 2.89.

Compound 122 Methyl 3-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-yl!ethoxy}phenylacetate ##STR143##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with methyl 3-hydroxyphenylacetate atreflux overnight, to give a white solid in 48% yield, mp 80°-82° C.; ¹ HNMR (CDCl₃) δ 7.13-7.24 (m, 6H), 6.81-7.01 (m, 6H), 5.17 (d, J=16.2 Hz,1H), 5.08 (d, J=16.2 Hz, 1H), 4.94 (dd, J=3.8, 9.3 Hz, 1H), 4.20-4.28(m, 2H), 3.70 (s, 3H), 3.60 (s, 2H), 2.57-2.61 (m, 1H), 2.29-2.37 (m,1H). IR 1735, 1680, 1503 cm⁻¹. MS 466 (MH⁺). Anal. Calc'd. for C₂₆ H₂₄ClNO₅ : C, 67.02; H, 5.19; N, 3.01. Found: C, 66.66; H, 5.31; N, 2.90.

Compound 123 3-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-yl!ethoxy}phenylacetic acid ##STR144##

Prepared from Compound 122 by method O but was acidified with conc. HCLand isolated as a light pink amorphous solid in 87% yield. ¹ H NMR(DMSO-d₆) δ 7.22-7.29 (m, 4H), 7.10-7.13 (m, 1H), 6.80-7.03 (m, 7H),5.17 (d, J=16.3 Hz, 1H), 5.07 (d, J=16.3 Hz, 1H), 4.94 (dd, J=3.9, 9.3Hz, 1H), 4.20-4.28 (m, 2H), 3.63 (s, 2H), 2.53-2.59 (m, 1H), 2.33 (ddt,J=14.5, 9.5, 4.8 Hz, 1H). IR 2950-3100 (br), 1728, 1659, 1502 cm⁻¹. MS452 (MH⁺). Anal. Calc'd. for C₂₅ H₂₂ ClNO₅ /0.6 H₂ O: C, 64.89; H, 5.05;N, 3.03. Found: C, 64.62; H, 4.91; N, 2.95.

Compound 124 Methyl 4-{4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl}butyrate##STR145##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with methyl 3-(4-hydroxyphenyl)butyrateat reflux overnight, and isolating a clear, amorphous solid in 46%yield; ¹ H NMR (CDCl₃) δ 7.10-7.20 (m, 3H), 6.99-7.08 (m, 3H with a 2Hdoublet (J=8.5 Hz) at 5 7.03), 6.83-6.94 (m, 3H), 6.75-6.80 (m, 3H witha 2H doublet (J=8.5 Hz) at 5 6.78), 5.09 (d, J=16.4 Hz, 1H), 5.00 (d,J=16.4 Hz, 1H), 4.94 (dd, J=3.9, 9.2 Hz, 1H), 4.10-4.25 (m, 2H), 3.60(s, 3H), 2.41-2.52 (m, 3H), 2.20-2.35 (m, 3H), 1.89 (quintet, J=7.5 Hz,2H). IR 1732, 1681, 1502 cm⁻¹. MS 494 (MH⁺).

Compound 125 4-{4-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl}butyricacid ##STR146##

Prepared from Compound 124 by Method O but acidified with conc. HCL andisolated as a white solid in 83% yield, mp129°-130° C.; ¹ H NMR(DMSO-d₆) δ 6.99-7.25 (m, 7H with a 2H doublet (J=8.5 Hz) at 8 7.10),6.91-6.96 (m, 3H), 6.81-6.87 (m, 3H with a 2H doublet (J=8.5 Hz) at 86.84), 5.16 (d, J=16.3 Hz, 1H), 5.08 (d, J=16.3 Hz, 1H), 4.94 (dd,J=3.8, 9.4 Hz, 1H), 4.18-4.26 (m, 2H), 2.58-2.64 (m, 3H), 2.25-2.39 (m,3H), 1.94 (quintet, J=7.5 Hz, 2H). IR 2900-3050 (br), 1697, 1678, 1503cm⁻¹. MS 480 (MH⁺), 422 (base). Anal. Calc'd. for C₂₇ H₂₆ ClNO₅ : C,67.57; H, 5.46; N, 2.92. Found: C, 67.19; H, 5.39; N, 2.78.

Compound 126 Methyl 3- 3-2-{4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl}ethoxy!phenyl!propionate##STR147##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with methyl3-(3-hydroxyphenyl)propionate at reflux overnight, and isolating a whitesolid in 51% yield, mp 92°-94° C.; ¹ H NMR (CDCl₃) δ 6.91-7.24 (m, 8H),6.76-6.83 (m, 4H), 5.18 (d, J=16.1 Hz, 1H), 5.08 (d, J=16.1 Hz, 1H),4.94 (dd, J=3.9, 9.4 Hz, 1H), 4.21-4.28 (m, 2H), 3.68 (s, 3H), 2.93 (t,J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.53-2.59 (m, 1H), 2.33 (ddt,J=9.4, 14.2, 4.7 Hz, 1H). IR 1724, 1677, 1503 cm⁻¹. MS 480 (MH⁺). Anal.Calc'd. for C₂₇ H₂₆ ClNO₅ : C, 67.57; H, 5.46; N, 2.92. Found: C, 67.38;H, 5.51; N, 2.71.

Compound 127 3- 3-2-{4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl}ethoxy!phenyl!propionicacid ##STR148##

Prepared from Compound 126 by method O but acidified with conc. HCL andisolated as a white solid in 93% yield, mp118°-119° C.; ¹ H NMR(DMSO-d₆) δ 7.18-7.24 (m, 4H), 7.10-7.12 (m, 1H), 6.90-7.04 (m, 3H),6.77-6.83 (m, 4H), 5.16 (d, J=16.0 Hz, 1H), 5.07 (d, J=16.0 Hz, 1H),4.95 (dd, J=3.8, 9.6 Hz, 1H), 4.21-4.29 (m, 2H), 2.94 (t, J=7.5 Hz, 2H),2.67 (t, J=7.5 Hz, 2H), 2.53-2.57 (m, 1H), 2.32 (ddt, J=9.8, 14.5, 4.7Hz, 1H). IR 3000-3200 (br), 1691, 1679, 1501 cm⁻¹. MS 466 (MH⁺). Anal.Calc'd. for C₂₆ H₂₄ ClNO₅ : C, 5 67.02; H, 5.19; N, 3.01. Found: C,66.63; H, 5.17; N, 2.87.

Compound 128 Methyl 2-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenylacetate##STR149##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with methyl 2-hydroxyphenylacetate atreflux overnight, and isolating a yellow oil. ¹ H NMR (CDCl₃) δ7.09-7.39 (m, 6H), 6.81-7.04 (m, 6H), 5.18 (d, J=16.3 Hz, 1H), 5.07 (d,J=16.3 Hz, 1H), 4.92 (dd, J=3.8, 9.6 Hz, 1H), 4.21-4.32 (m, 2H), 3.60(s, 2H), 2.54-2.62 (m, 2H), 2.33 (ddt, J=14.4, 9.6, 4.9 Hz, 1H).

Compound 129 2-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenylaceticacid ##STR150##

Prepared from Compound 128 by method O but acidified with conc. HCL andisolated as a white solid in 89% yield, mp 140-142° C.; ¹ H NMR(DMSO-d₆) δ 7.07-7.25 (m, 6H), 6.84-7.00 (m, 6H), 5.13 (s, 2H), 5.01(dd, J=4.0, 9.2 Hz, 1H), 4.20-4.34 (m, 2H), 3.68 (d, J=16.0 Hz, 1H),3.59 (d, J=16.0 Hz, 1H), 2.40-2.59 (m, 1H), 2.28-2.38 (m, 1H). IR3000-3200 (br), 1722, 1677, 1498 cm⁻¹. MS 452 (MH⁺), 300 (base). Anal.Calc'd. for C₂₅ H₂₂ ClNO₅ /0.2 H₂ O: C, 65.92; H, 4.96; N, 3.07. Found:C, 65.75; H, 4.99; N, 2.88.

Compound 130 4-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}benzaldehyde##STR151##

Prepared from method L, which was modified by coupling intermediate10488-22 (Reference Example 66) with 4-hydroxybenzaldehyde at refluxovernight. The product was isolated as a white solid afterchromatography in 30% yield, mp 130°-131° C.; ¹ H NMR (CDCl₃) δ 9.89 (s,1H), 7.85 (d, J=8.8 Hz, 2H), 7.23-7.30 (m, 3H), 7.10-7.15 (m, 1H),6.92-7.05 (m, 5H), 6.83 (dd, J=1.4, 8.7 Hz, 1H), 5.20 (d, J=16.2 Hz,1H), 5.07 (d, J=16.2 Hz, 1H), 4.93 (dd, J=4.1, 9.1 Hz, 1H), 4.25-4.42(m, 2H), 2.58-2.70 (m, 1H), 2.40 (ddt, J=10.0, 14.2, 5.0 Hz, 1H). IR1700, 1674, 1598 cm⁻¹. MS 422 (MH⁺). Anal. Calc'd. for C₂₄ H₂₀ ClNO₄ :C, 68.33; H, 4.78; N, 3.32. Found: C, 68.01; H, 4.82; N, 3.27.

Compound 131 Methyl 2- 4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl!glycolate##STR152##

Bromoform (0.31 mL, 3.54 mmol) was added dropwise under a nitrogenatmosphere to Compound 130 (1.15 g, 2.73 mmol), lithium chloride (0.231g, 5.45 mmol), potassium hydroxide (0.611 g, 10.9 mmol) and water (4 mL)in dioxane (4 mL). After heating in an oil bath at 40° C. overnight, thereaction was acidified to pH=1 with HCl (1N) and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with water(2×50 mL), dried (MgSO₄), filtered and evaporated to afford impurehydroxyacid as a yellow oil. A solution of acetyl chloride (0.4 mL) inmethanol (10 mL) was added to the crude acid and the reaction stirred atroom temperature under a nitrogen atmosphere overnight. The methanol wasevaporated and the reside dissolved in ether (200 mL). This was washedwith saturated NaHCO₃ (2×50 mL), dried (MgSO₄), filtered and evaporated.The α-hydroxyester was obtained after silica gel chromatgraphy (elutingwith EtOAc/CH₂ Cl₂), in 52% overall yield, ¹ H NMR (CDCl₃) δ 7.32 (d,J=8.7 Hz, 2H), 7.23-7.26 (m, 3H), 7.10-7.15 (m, 1H), 6.93-7.03 (m, 3H),6.91 (d, J=8.7 Hz, 2H), 6.81-6.89 (m, 1H), 5.18 (d, J=16.2 Hz, 1H), 5.13(d, J=5.6 Hz, 1H), 5.07 (d, J=16.2 Hz, 1H), 4.93 (dd, J=3.9, 9.4 Hz,1H), 4.17-4.32 (m, 2H), 3.76 (s, 3H), 3.40 (d, J=5.6 Hz, 1H,exchangeable), 2.53-2.64 (m, 1H), 2.33 (ddt, J=14.4, 9.4, 4.8 Hz, 1H).

Compound 132 2- 4-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl!glycolicacid ##STR153##

Prepared from Compound 131 by method O but acidified with conc. HCL andisolated as a pale yellow solid, in 85% yield, mp 54°-56° C.;¹ H NMR(DMSO-d₆) δ 7.36 (d, J=8.6 Hz, 2H), 7.23-7.26 (m, 4H), 7.09-7.12 (m,1H), 6.81-7.01 (m, 5H), 5.20 (s, 1H), 5.16 (d, J=16.6 Hz, 1H), 5.07 (d,J=16.6 Hz, 1H), 4.93 (dd, J=4.0, 9.2 Hz, 1H), 4.20-4.27 (m, 2H), 3.20(br s, 1H, exchangeable), 2.53-2.62 (m, 1H), 2.30-2.38 (m, 1H). IR3300-3400 (br), 2800-3150 (br), 1731, 1671, 1512 cm⁻¹. MS (FAB) 468(MH⁺), 300 (base). Anal. Calc'd. for C₂₅ H₂₂ ClNO₆ /0.5 H₂ O: C, 62.96;H, 4.86; N, 2.94. Found: C, 62.80; H, 4.99; N, 2.92.

Compound 133 Methyl 2-chloro-2- 4-{2-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxy}phenyl!acetate##STR154##

Thionyl chloride (0.091 mL, 1.24 mmol) was added to Compound 130 (0.460g, 0.95 mmol) in benzene (10 mL), followed by pyridine (0.093 mL, 1.15mmol) under a nitrogen atmosphere at room temperature. After stirringovernight, the solvent was evaporated and the residue poured into water(50 mL). This mixture was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with water (3×50 mL), dried (MgSO₄),filtered and evaporated to afford corresponding chloride as a clear gelin 82% yield; ¹ H NMR (DMSO-d₆) δ 7.42 (d, J=8.7 Hz, 2H), 7.23-7.29 (m,3H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 2H), 6.90-6.97 (m, 3H with a 2Hdoublet (J=8.7 Hz) at 5 6.92), 6.82 (d, J=7.4 Hz, 1H), 5.34 (s, 1H),5.18 (d, J=16.2 Hz, 1H), 5.08 (d, J=16.2 Hz, 1H), 4.93 (dd, J=4.0, 9.4Hz, 1H), 4.19-4.33 (m, 2H), 3.78 (s, 3H), 2.54-2.65 (m, 1H), 2.34 (ddt,J=14.3, 9.4, 4.8 Hz, 1H).

Compound 134 5- 4-{2-4-(3-Chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl!ethoxyphenyl!thiazolidine-2,4-dione##STR155##

Thiourea (56 mg, 0.74 mmol) was added to Compound 133 (0.185 g, 0.37mmol) in 2-methoxyethanol (3 mL), . The reaction was heated in an oilbath at 110° C. for 3 h. After cooling, HCl (1N, 2.5 mL) was added thereaction heated at 100° C. overnight. The cooled reaction was dilutedwith water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layers were washed with water (3×50 mL), dried (MgSO₄), filteredand evaporated to afford the thiazolidindione as pale yellow foam in 64%yield, mp 70°-72° C.; ¹ H NMR (DMSO-d₆) δ 8.05 (br s, 1H), 7.35 (d,J=8.7 Hz, 2H), 7.23-7.25 (m, 3H), 7.11-7.15 (m, 1H), 6.81-7.02 (m, 5Hwith a 2H doublet (J=8.7 Hz) at δ 6.96), 6.83 (d, J=8.6 Hz, 1H), 5.36(s, 1H), 5.19 (d, J=16.2 Hz, 1H), 5.07 (d, J=16.2 Hz, 1H), 4.94 (dd,J=4.0, 9.1 Hz, 1H), 4.22-4.30 (m, 2H), 2.54-2.62 (m, 1H), 2.32-2.40 (m,1H). IR 1756, 1698, 1500 cm⁻¹. MS 509 (MH⁺).

Compound 135 3,4-Dihydro-2-{2-4-(2-guanidinoethyl)phenoxy!ethyl}-6-methylsulfonamido-4-(3-chlorobenzyl)-3-oxo-2H-1,4-benzoxazine##STR156## Method P

Compound 92 was heated at reflux for 10 hours with methanesulfonylchloride (1.1 eq) DMAP (0.1 eq) in CH₂ Cl₂ (10 mL). The resultingmixture was diluted with water and title compound was isolated byfiltration, mp (dec)>121° C.; IR (KBr) 3240, 1667, 1613, 1512, 1475,1349, 1245, 1178, 865 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 9.63 (br s, 1H), 8.07(br s, 1H), 7.43 (br s, 2H), 7.35 (m, 4H), 7.20 (m, 3H), 7.01 (d, 1H,J=8.6 Hz), 6.89 (m, 2H), 6.82 (dd, 2H, J=2.2, 8.5 Hz), 5.16 (d, 1H,J=16.5 Hz), 5.03 (d, 1H, J=16.5 Hz), 4.97 (dd, 1H, J=4.2, 8.8 Hz), 4.16(m, 2H), 3.25 (m, 2H), 2.79 (s, 3H), 2.70 (t, 2H, J=7.2 Hz), 2.35 (m,1H), 2.22 (m, 1H). Anal. Calc'd for C₂₇ H₃₀ ClNO₅ S. 1.7 HCl: C 51.15, H5.04, N 11.05. Found: 51.47, H 5.14, N 10.78.

Compound 136 2-{2-4-(2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl)-3,4-dihydro-4-(3-methylsulfonamidobenzyl)-3-oxo-2H-1,4-benzoxazine##STR157##

Prepared from Compound 101 by method P to give a tan solid (dec)>79° C.;MS (FAB) MH⁺ 738;IR (KBr) 3325, 2977, 1723, 1687, 1612, 1501, 1410,1330, 1245, 1151, 1057, 971, 688 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 11.47 (br s,1H), 8.37 (brt, 1H), 7.31 (m, 1H), 7.11 (m, 4H), 7.05-6.89 (m, 3H), 6.83(m, 3H), 6.45 (br s, 1H), 5.14 (d, 2H, J=7.2 Hz), 4.94 (dd, 1H, J=4.0,9.3 Hz), 4.20 (m, 2H), 3.62 (m, 2H), 2.94 (s, 3H), 2.81 (t, 2H, J=7.2Hz), 2.55 (m, 1H), 2.34 (m, 1H), 1.60 (br s, 1H), 1.50 (s, 9H), 1.48 (s,9H). Anal. Calc'd for C₃₇ H₄₇ N₅ O₉ S 0.9 H₂ O: C 58.93, H 6.52, N 9.29.Found C 59.19, H 6.58, N 9.00.

Compound 137 2-{2-4-(2-Guanidinoethyl)-phenoxy!ethyl}-3,4-dihydro-4-(3-methylsulfonamidobenzyl)-3-oxo-2H-1,4-benzoxazine##STR158##

Prepared from Compound 136 by method K in 94% yield, mp (dec)>95° C.; MS(FAB) MH⁺ 538;IR (KBr) 3156, 1664, 1500, 1468, 1402, 1327, 1243, 1147,1052, 978, 751, 690, 514 cm⁻¹ ; ¹ H NMR (DMSO-d6) δ 9.82 (br s, 1H),7.64 (br t, 1H), 7.55-6.85 (br s, 3H), 7.28 (t, 1H, J=7.8 Hz), 7.20 (d,2H, J=8.5 Hz), 7.09 (s, 1H), 7.05 (m, 2H), 6.99 (m, 4H), 6.92 (d, 2H,J=8.5 Hz), 5.19 (d, 1H, J=16.6 Hz), 5.09 (d, 1H, J=16.6 Hz), 4.94 (dd,1H, J=4.11, 9.0 Hz), 4.19 (m, 2H), 3.33 (m, 2H), 2.93 (s, 3H), 2.72 (t,2H, J=7.4 Hz), 2.32 (m, 1H), 2.22 (m, 1H). Anal. Calc'd for C₂₇ H₃₁ N₅O₅ S: C 55.32, H 5.93, N 11.32. Found: C 55.34, H 5.86, N 11.34.

Compound 138 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl)-3,4-dihydro-3-oxo-4-pentyl-2H-1,4-benzoxazine##STR159##

Prepared from 10840-185 (Reference Example 60) by method L using equalequivalents of reagents and was isolated in 42% yield as a white foamafter SiO₂ chromatography (hexane/CH₂ Cl₂, 1/3); IR (KBr) 3334, 2977,2932, 2872, 1685, 1639, 1615, 1501, 1409, 1366, 1331, 1131, 1058, 748cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.91 (t, J=6.8 Hz, 3H), 1.32-1.40 (m, 4H), 1.48(s, 9H), 1.51 (s, 9H), 1.61-1.72 (m, 2H), 2.17-2.30 (m, 1H), 2.43-2.55(m, 1H), 2.81 (t, J=7.2 Hz, 2H), 3.63 (q, J=7.1 Hz, 2H), 3.92 (t, J=6.8Hz, 2H), 4.13-4.25 (m, 2H), 4.79 (dd, J=9.20, 4.0 Hz, 1H), 6.84 (d,J=8.5 Hz, 2H), 6.96-7.07 (m, 4H), 7.12 (d, J=8.6 Hz, 2H), 8.37 (br t,J=4.3 Hz, 1H), 11.48 (br s, 1H); Anal. Calc'd for C₃₄ H₄₈ N₄ O₇ : C,65.36; H, 7.74; N, 8.97. Found: C, 65.23; H, 7.70; N, 8.98.

Compound 139 3,4-Dihydro-2-(2-4-(2-guanidinoethyl)-phenoxy!ethyl}-4-(4-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR160##

Prepared from Compound 93 by method K to give a solid: in 68% yield: mp:dec.>101° C.; MS: FAB MH⁺ at 524; IR (KBr) 3433,1671, 1600,1525, 1501,1468, 1398, 1344, 1253, 1065, 894, 810 cm⁻¹ ; ¹ H NMR (DMSO-d6/TMS) δ8.20(d, 2H, J=8.2 Hz), 7.54(d, 2H, J=8.5 Hz), 7.45-6.60(v. br. s., 4H),7.38(s, 1H), 7.29(s, 1H), 7.18(m, 2H), 7.05(m, 2H), 6.97(m, 3H), 5.36(d,1H, J=18.0 Hz), 5.22(1H, J=18.0 Hz), 4.99(m, 1H), 4.26(m, 2H), 3.35(m,2H), 2.68(t, 2H, J=6.3 Hz), 2.40(m, 1H), 2.28(m, 1H).

Compound 140 2-{2- 4-2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl!phenoxy!ethyl}-3,4-dihydro-4(4-methoxybenzyl)-3-oxo-2H-1,4-benzoxazine##STR161##

Prepared by method L using intermediate 10508-19 (Reference Example 47)and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine to givethe title compound as a white foam: Anal. Calc'd for C₂₇ H₄₆ N₄ O₈ : C,65.86; H, 6.87; N, 8.3. Found: C, 65.51; H, 7.02; N, 8.27.

Compound 141 3,4-Dihydro-4-(2,4-dichlorobenzyl)-2-{2-4-(2-guanidinoethyl)-phenoxy!ethyl}-3-oxo-2H-1,4-benzoxazine ##STR162##

Prepared by method L using intermediate 10005-181-1 (Reference Example48) and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine andmethod K to give a solid: Anal. Calc'd for C₂₆ H₄₂₆ Cl₂ N₄ O₃.HCl.0.75H₂ O: C, 55.43; H, 5.10; N, 9.94. Found: C, 55.43; H, 5.05; N, 9.75.

Compound 142 2- 2-4-(3-Aminopropyl)phenoxy!ethyl!-4-(4-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR163##

Prepared from intermediate 10353-28-1 (Reference Example 41) and 4-3-(N-t-butoxycarbonylamino)propyl!phenol by methods J and K to give thetitle compound as a yellow solid (11% yield).m.p.=95°-97° C.; MS (FAB)MH⁺ 451; IR (Kbr) 1250, 1400, 1500, 1590, 1680, 2040, 2950, 3400 cm⁻¹ ;1H (NMR) 7.40 (d, J=8.47 Hz, 2H), 7.30 (d, J=8.48 Hz, 2H), 2.62 (t,J=7.54 Hz, 2H), 2.76 (t, J=7.52 Hz, 2H), 7.23 (t, J=8.12 Hz, 1H), 6.81(d, J=7.37 Hz, 3H), 7.91 (br. s, 2H), 6.99-7.08 (m, 4H), 4.19-4.20 (m,2H), 2.33-2.49 (m, 1H), 2.19-2.30 (m, 1H), 1.82-1.87 (m, 2H), 5.18 (dd,J=16.48and 23.23 Hz, 2H), 4.98 (dd, J=4.15 and 8.75 Hz, 1H). Anal.Calc'd for C26H28N203Cl2: C 62.68, H 5.91, N 5.62. Found: C 62.97, H5.78, N 5.37.

Compound 143 2-{2-4-(2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-3,4-dihydro-7-nitro-4-(2-nitrobenzyl)3-oxo-2H-1,4-benzoxazine ##STR164##

Prepared by method L using intermediate 11653-142 (Reference Example 69)and N,N'-di-t-butoxycarbonyl-2(4-hydroxyphenyl)ethyl guanidine, andmethod K to give the title compound as a solid in 13% yield; m.p.:dec.>128° C.; MS (FAB) MH⁺ 735; IR (KBr) 3323, 3087, 2977, 1723, 1690,1641, 1613, 1530, 1513, 1476, 1418, 1395, 1240, 1154, 941 cm⁻¹ ; ¹ H NMR(CDCl₃ /TMS) δ 11.43(s, 1H), 8.37(br. t., 1H), 8.24(dd, 1H, J=2.1, 7.4Hz), 7.94(d, 1H, J=2.5 Hz), 7.84(dd, 1H, J=2.5, 8.9 Hz), 7.52(m, 2H),7.14(d, 2H, J=8.6 Hz), 7.08(d, 1H, J=9.1 Hz), 6.84(d, 2H, J=8.6 Hz),6.77(d, 1H, J=8.9 Hz), 5.68(d, 1H, J=18.1 Hz), 5.56(d, 1H, J=18.1 Hz),5.10(dd, 1H, J=4.0, 8.9 Hz), 4.23(m, 2H), 3.64(m, 2H), 2.82(t, 2H, J=7.3Hz), 2.63(m, 1H), 2.40(m, 1H), 1.50(s, 9H), 1.48(s, 9H).

Compound 144 2- 2-4-(2-(t-Butoxycarbonylamino)ethyl)phenoxy!ethyl!-4-(3-chlorobenzyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine##STR165##

Methanesulfonyl chloride (0.8 ml, 1.5 eq.) was added in one portion to asolution of intermediate 10353-191-1 (2.0 g, 1 eq.,Reference Example40), DMAP (0.33 g, 0.4 eq.) and triethylamine (1.2 ml, 1.5 eq.) in 30 mlCH₂ C₂. This mixture was stirred for 15 min and diluted with an equalpart of water. The resulting organic layer was washed with brine, dried(MgSO₄) and concentrated in vacuo to give the mesylate. This mesylatewas treated with 4- 2-(N-t-butoxycarbonylamino)ethyl!phenol followingthe procedures of method J to give the title compound as a solid: mp91°-92° C.

Compound 145 2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-4-(2-chlorobenzyl)-3,4-dihydro-2H-1,4-benzoxazine##STR166##

Prepared by method L using intermediate 10353-76 (Reference Example 89)and N,N'-di-t-butoxycarbonyl-2-(4-hydroxyphenyl)methyl guanidine andmethod K with the following modifications. The bis-Boc-protectedMitsunobu coupling product was isolated by dissolving the crude productresidue in aqueous methanol and treating with a dropwise addition of 2NNaOH until basic. The precipitate was collected by filtration. Theresulting product was dissolved in ether, washed sequentially with 1NHCl, sat'd NaHCO₃, and brine, dried over Na₂ SO₄ and concentrated undervacuum and used without further purification. The deprotected productwas isolated the bicarbonate salt (light brown solid) in 22% yield as atan solid, single homogeneous peak by HPLC (PDA detection) 15 cm C18column, eluting with 55/45 H₂ O (5% NH₄ OH, 5% HOAC)/CH₃ CN; MS (Cl) 451(MH⁺); IR (KBr) 3314, 3036, 2923, 1682, 1608, 1581, 1511, 14658, 1443,1392, 1352, 1302, 1244, 1223, 1175, 1046, 742 cm⁻¹.

Compound 146 2-{2-4-(2-(N,N-Bis-tert-butoxycarbonylguanidino)ethyl)-phenoxy!ethyl}-4-(3-chlorobenzyl)-3,4-dihydro-6-methoxy-3-oxo-2H-1,4-benzoxazine##STR167##

Prepared from intermediate 12168-25-1 (Reference Example 43) andN,N'-di-t-butoxycarbonyl-2(4-hydroxy-phenyl)ethyl guanidine by method Lin 92% yield. Crystallization from EtOH/H₂ O afforded the pure productas a white solid. nmr (CDCl₃) δ 11.28 (s, 1H), 7.23 (m, 3H), 7.12 (m,1H), 7.12 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.9 Hz, 1H), 6.86 (d, J=9.0 Hz,2H), 6.51 (dd, J=8.4, 2.9 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 5.15 (d,J=16.9 Hz, 1H), 5.05 (d, J=16.9 Hz, 1H), 4.89 (dd, J=10.0, 4.1 Hz, 1H),4.20 (m, 2H), 3.64 (m, 2H), 2.82 (apparent t, J=7.3 Hz, 2H), 2.55 (m,1H), 2.32 (m, 1H), 1.52 (s, 9H), 1.50 (s, 9H).

Compound 147 4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-4-(2-guanidinoethyl)-phenoxy!ethyl}-6-methoxy-3-oxo-2H-1,4-benzoxazine##STR168##

Prepared from Compound 146 by method K and isolated by trituration withEt₂ O to afford a hydroscopic tan solid in 76% yield nmr (DMSO-d₆) δ7.43 (br s, 1H), 7.4-6.5 (v br s, 4H), 7.35 (m, 3H), 7.22 (m, 1H), 7.19(d, J=8.5 Hz, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.61(d, J=2.5H), 2.58 (dd, J=9.0, 3.1 Hz, 1H), 5.21 (d, J=17.0 Hz, 1H), 5.18(d, J=17.0 Hz, 1H), 4.96 (dd, J=8.8, 4.1 Hz, 1H), 4.19 (m, 2H), 3.64 (s,3H), 3.30 (m, 2H), 2.40 (apparent t, J=6.8 Hz, 2H), 2.39 (m, 1H), 2.23(m, 1H).

Compound 148 2-{2-4-(2-guanidinoethyl)-phenoxy!ethyl}-3,4-dihydro-6-fluoro-4-(3-nitrobenzyl)-3-oxo-2H-1,4-benzoxazine##STR169##

Prepared from Compound 102 by method K to give the title compound as asolid: MP: dec.>76° C.; MS (FAB) MH⁺ 508; IR (KBr) 3349, 3180, 2932,2872, 1621, 1531, 1506, 1469, 1296, 948, 838 cm⁻¹ ; ¹ H (NMR) δ 8.20(s,1H), 8.13(d, 1H, J=7.9 Hz), 7.66(m, 2H), 7.53(br.s., 1H),7.50-6.60(v.br.s., 3H), 7.19(d, 2H, J=8.4 Hz), 7.09(m, 2H), 6.90(d, 2H,J=8.4 Hz), 6.85(m, 1H), 5.32(s, 2H), 5.01(dd, 1H, J=4.3, 8.7 Hz),4.18(m, 2H), 3.28(m, 2H), 2.71(t, 2H, J=7.2 Hz), 2.39(m, 1H), 2.25(m,1H).

We claim:
 1. A compound selected from those of Formula 1: ##STR170##wherein the moiety Q is a fused pyridyl moiety; Z₁ is hydrogen, halogen,C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy, amino, nitro,sulfonylamino or trifluoromethyl;Z₂ is hydrogen or a halogen; X ishydrogen or oxygen; A is C₁ -C₅ alkyl, --CH₂ phenyl, --CH₂ thienyl,--CH₂ pyridyl, --CH₂ furyl, or -ethyl piperidine; wherein said phenyl,thienyl, pyridyl, furyl or piperidine moiety is optionally substitutedwith (C₁ -C₆)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy,halogen, dihalogen, nitro, amino, carboxyl or carbomethoxy; n is aninteger from 0-3; Y is a moiety selected from:(a) --NHR₁ R₂,--N⁺ R₁ R₂R₃ ; ##STR171## (c) --CO₂ H, --CHO; (d) --CH(R₆)CO₂ H, --CH(R₆)CO₂ CH₃,--CH═CHR₇, --CH═C(CO₂ H)₂ ; (e) a moiety of the formula: ##STR172## (f)5-tetrazolyl; wherein R₁, R₂ and R₃ are independently hydrogen, C₁ -C₆alkyl, or t-butoxycarbonyl; R₄ and R₅ are independently t-butoxycarbonylor hydrogen or R₄ and R₅ may be joined together to form an imnidazoline,imidazolyl or pyrimidine ring; R₆ is hydrogen, hydroxy or chloro; R₇ isCO₂ H or C(O)NH(CH₂)_(p) OH wherein p is an integer from 1-4; and thepharmaceutically acceptable salts, esters and pro-drug forms thereof. 2.A compound according to claim 1 wherein the moiety Y is selectedfrom:(a) --NHR₁ R₂, --N⁺ R₁ R₂ R₃ ; ##STR173## (c) --CO₂ H; (d)--CH(R₆)CO₂ H, or (e) a moiety of the formula: ##STR174## wherein R₁, R₂and R₃ are independently hydrogen, C₁ -C₆ alkyl or t-butoxycarbonyl; R₄and R₅ are independently t-butoxycarbonyl or hydrogen; R₆ is hydrogen orhydroxy; and the pharmaceutically acceptable salts, esters and pro-drugforms thereof.
 3. The compound according to claim 1,4-(3-Chlorobenzyl)-3,4-dihydro-2- 2-4-(2-guanidinoethyl)phenoxy!ethyl!-3-oxo-2H-pyrido 3,2-b!-1,4-oxazine.4. A pharmaceutical composition for treating bacterial infectionscomprising an effective amount of a compound selected from claim 1 inassociation with a pharmaceutically acceptable carrier.
 5. A method oftreating bacterial infections in mammals by administering to a mammalsuffering from such infection a therapeutically effective amount of acompound selected from claim
 1. 6. A method of potentiating the activityof an antibacterial agent in mammals by administering said antibacterialagent in combination with a compound selected from claim
 1. 7. Apharmaceutical composition for treating bacterial infections comprisingan antibacterial agent and a compound selected from claim 1 intherapeutically effective amounts in association with a pharmaceuticallyacceptable carrier.
 8. A method of preparing a compound of the Formula1: ##STR175## wherein the moiety Q is a fused pyridyl moiety; Z₁ ishydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, phenyl, hydroxy, amino,nitro, sulfonylamino or trifluoromethyl;Z₂ is hydrogen or a halogen; Xis hydrogen or oxygen; A is C₁ -C₅ alkyl, --CH₂ phenyl, --CH₂ thienyl,--CH₂ pyridyl, --CH₂ furyl, or -ethyl piperidine; wherein said phenyl,thienyl, pyridyl, furyl or piperidine moiety is optionally substitutedwith (C₁ -C₆)alkyl, benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy,halogen, dihalogen, nitro, amino, carboxyl or carbomethoxy; n is aninteger from 0-3; Y is a moiety selected from:(a) --NHR₁ R₂, --N⁺ R₁ R₂R₃ ; ##STR176## (c) --CO₂ H, --CHO; (d) --CH(R₆)CO₂ H, --CH(R₆)CO₂ CH₃,--CH═CHR₇, --CH═C(CO₂ H)₂ ; (e) a moiety of the formula: ##STR177## (f)5-tetrazolyl; wherein R₁, R₂ and R₃ are independently hydrogen, C₁ -C₆alkyl, or t-butoxycarbonyl; R₄ and R₅ are independently t-butoxycarbonylor hydrogen or R₄ and R₅ may be joined together to form an imidazoline,imidazolyl or pyrimidine ring; R₆ is hydrogen, hydroxy or chloro; R₇ isCO₂ H or C(O)NH(CH₂)_(p) OH wherein p is an integer from 1-4; and thepharmaceutically acceptable salts, esters and pro-drug forms thereof,which comprises reacting a compound of the formula: ##STR178## wherein Qis fused pyridyl with a compound of the formula: ##STR179## wherein themoiety Y is protected or unprotected, in a suitable solvent in thepresence of an appropriate phosphine and azodicarbonyl reagent, andwhere Y is protected, removing the protecting group and recovering thecompound of formula
 1. 9. A compound of the formula: ##STR180## whereinthe Q moiety is fused pyridyl; Z₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy, phenyl, hydroxy, amino, nitro, sulfonylamino ortrifluoromethyl;Z₂ is hydrogen or a halogen; X is hydrogen or oxygen; Ais C₁ -C₅ alkyl, --CH₂ phenyl, --CH₂ thienyl, --CH₂ pyridyl, --CH₂furyl, or -ethyl piperidine; wherein said phenyl, thienyl, pyridyl,furyl or piperidine moiety is optionally substituted with (C₁ -C₆)alkyl,benzyl, oxybenzyl, phenoxy, hydroxy, alkoxy, halogen, dihalogen, nitro,amino, carboxyl or carbomethoxy; and R₈ is hydrogen or a hydroxyprotecting group.